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Interplay between Brain Pericytes and Endothelial Cells in Dementia

  • Tessa V. Procter
    Affiliations
    Centre for Regenerative Medicine, Institute for Regeneration and Repair, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, United Kingdom
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  • Anna Williams
    Affiliations
    Centre for Regenerative Medicine, Institute for Regeneration and Repair, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, United Kingdom

    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
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  • Axel Montagne
    Correspondence
    Address correspondence to Axel Montagne, Ph.D., UK Dementia Research Institute, Centre for Clinical Brain Sciences, The University of Edinburgh, Chancellor's Bldg., 49 Little France Crescent, Edinburgh EH16 4SB, United Kingdom.
    Affiliations
    UK Dementia Research Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom

    Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
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      Prevalence of dementia continues to increase because of the aging population and limited treatment options. Cerebral small vessel disease and Alzheimer disease are the two most common causes of dementia with vascular dysfunction being a large component of both their pathophysiologies. The neurogliovascular unit, in particular the blood-brain barrier (BBB), is required for maintaining brain homeostasis. A complex interaction exists among the endothelial cells, which line the blood vessels and pericytes, which surround them in the neurogliovascular unit. Disruption of the BBB in dementia precipitates cognitive decline. This review highlights how dysfunction of the endothelial-pericyte crosstalk contributes to dementia, and focuses on cerebral small vessel disease and Alzheimer disease. It also examines loss of pericyte coverage and subsequent downstream changes. Furthermore, it examines how disruption of the intimate crosstalk between endothelial cells and pericytes leads to alterations in cerebral blood flow, transcription, neuroinflammation, and transcytosis, contributing to breakdown of the BBB. Finally, this review illustrates how cumulation of loss of endothelial-pericyte crosstalk is a major driving force in dementia pathology.
      Dementia is characterized by a gradual cognitive impairment with additional symptoms, such as depression and changes to balance and gait.
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      suggesting that vascular dysfunction is a major contributing factor in both. Vascular dysfunction can take many forms that involve many cells comprising the neurogliovascular unit (NVU) and include disruption of the blood-brain barrier (BBB), which plays a vital role in maintaining cerebral homeostasis. However, this review focuses on how the complex interactions between endothelial cells lining the blood vessels and pericytes closely apposed to the endothelial cells on the abluminal side contribute to BBB disruption, a central pathologic mechanism in these two important dementias.

      The BBB in Health

      Blood vessels throughout the body are normally partly permeable to allow the exchange of nutrients, solutes, and chemical signals between tissue and the blood, which are vital for keeping cells alive. However, the brain microenvironment is different from the rest of the body and requires tighter control provided by the BBB. Substance movement can occur paracellularly (between endothelial cells) or transcellularly (across endothelial cells), and the BBB tightly regulates the two types of substance movement via junctional complexes between endothelial cells and through expression of membrane receptors and pumps, with limited passive diffusion.
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      Furthermore, the BBB allows separation of peripheral and central neurotransmitters, avoiding potential cross-signaling.
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      Pathogens, plasma proteins, and immune cells from the blood can have severe detrimental consequences if present within the brain, and disruption to the BBB is a major component of many neurologic diseases, including AD and cSVD.
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      The BBB comprises various components, commonly referred to as the NVU (Figure 1), including endothelial cells, pericytes, basement membrane, astrocyte end-feet, and surrounding oligodendrocytes and microglia, and links to neurons in a process called neurovascular coupling in which increased neuronal activity leads to increased blood flow to that area.
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      The NVU is unique in that its cellular components are in close and sometimes direct contact with one another, allowing for intimate crosstalk.
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      Structure and function of the blood-brain barrier.
      Endothelial cells line the blood vessels, and pericytes are mesenchymal-derived cells on the brain side of endothelial cells. Pericytes are found encircling capillaries as well as precapillary arterioles and postcapillary venules, whereas vascular smooth muscle cells (VSMCs) are found in larger vessels.
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      Endothelial/pericyte interactions.
      Collectively, pericytes and VSMCs are known as vascular mural cells (VMCs).
      Figure thumbnail gr1
      Figure 1Components of the neurogliovascular unit (NVU) and changes that occur in cerebral small vessel disease (cSVD) and Alzheimer disease (AD). The components of the NVU play an important role in maintaining the blood-brain barrier (BBB) in health. In dementia, changes, in particular to the endothelial cells and pericytes, lead to loss of function and BBB breakdown. Subsequently, the surrounding astrocytes, neurons, and oligodendrocytes get damaged, contributing to pathologic findings. Figure generated with Biorender.com (Biorender, Toronto, Ontario, Canada).
      In human tissue, pericytes form two subtypes with enriched gene expression of either transmembrane transporters or extracellular matrix (ECM) regulation genes.
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      In addition, pericyte morphology plays an important role in maintaining BBB integrity because pericytes in the median eminence (ME), where BBB leakage naturally occurs, have a more irregular shape and less prominent nucleus compared with cortical tissue with a functional BBB.
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      subdivided pericytes into ensheathing pericytes located on larger diameter precapillary arterioles with shorter cell lengths and α-smooth muscle actin (α-SMA), and mesh pericytes and thin-strand pericytes located on smaller diameter capillaries with longer cell lengths, and no detectable α-SMA. They argue that ensheathing pericytes are transitional mural cells with characteristics of both VSMCs and pericytes, whereas mesh and thin-strand pericytes comprise the capillary pericytes.
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      Much of the literature makes no distinctions between pericyte subtypes because of not assessing morphologic differences. Furthermore, platelet-derived growth factor receptor β (PDGFR-β), which is expressed in all pericyte subtypes,
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      is frequently used as a pericyte marker. However, other CNS cell types have also been found to express PDGFR-β, such as perivascular fibroblast–like cells
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      Clinical Evidence of BBB Disruption in AD and cSVD

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      • Chung A.W.
      • Rich P.
      • Mackinnon A.D.
      • Morris R.G.
      • Barrick T.R.
      • Markus H.S.
      Cerebral microbleeds and cognition in patients with symptomatic small vessel disease.
      • Cordonnier C.
      • van der Flier W.M.
      Brain microbleeds and Alzheimer's disease: innocent observation or key player?.
      • Verbeek M.M.
      • Otte-Höller I.
      • Westphal J.R.
      • Wesseling P.
      • Ruiter D.J.
      • de Waal R.M.
      Accumulation of intercellular adhesion molecule-1 in senile plaques in brain tissue of patients with Alzheimer's disease.
      • Bailey E.L.
      • McBride M.W.
      • Beattie W.
      • McClure J.D.
      • Graham D.
      • Dominiczak A.F.
      • Sudlow C.L.
      • Smith C.
      • Wardlaw J.M.
      Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.
      • Blanchard J.W.
      • Bula M.
      • Davila-Velderrain J.
      • Akay L.A.
      • Zhu L.
      • Frank A.
      • Victor M.B.
      • Bonner J.M.
      • Mathys H.
      • Lin Y.T.
      • Ko T.
      • Bennett D.A.
      • Cam H.P.
      • Kellis M.
      • Tsai L.H.
      Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes.
      • Török O.
      • Schreiner B.
      • Schaffenrath J.
      • Tsai H.C.
      • Maheshwari U.
      • Stifter S.A.
      • Welsh C.
      • Amorim A.
      • Sridhar S.
      • Utz S.G.
      • Mildenberger W.
      • Nassiri S.
      • Delorenzi M.
      • Aguzzi A.
      • Han M.H.
      • Greter M.
      • Becher B.
      • Keller A.
      Pericytes regulate vascular immune homeostasis in the CNS.
      • Daneman R.
      • Zhou L.
      • Kebede A.A.
      • Barres B.A.
      Pericytes are required for blood-brain barrier integrity during embryogenesis.
      • Rouhl R.P.
      • Damoiseaux J.G.
      • Lodder J.
      • Theunissen R.O.
      • Knottnerus I.L.
      • Staals J.
      • Henskens L.H.
      • Kroon A.A.
      • de Leeuw P.W.
      • Tervaert J.W.
      • van Oostenbrugge R.J.
      Vascular inflammation in cerebral small vessel disease.
      • Kim Y.
      • Kim Y.K.
      • Kim N.K.
      • Kim S.H.
      • Kim O.J.
      • Oh S.H.
      Circulating matrix metalloproteinase-9 level is associated with cerebral white matter hyperintensities in non-stroke individuals.
      • Huang C.W.
      • Tsai M.H.
      • Chen N.C.
      • Chen W.H.
      • Lu Y.T.
      • Lui C.C.
      • Chang Y.T.
      • Chang W.N.
      • Chang A.Y.
      • Chang C.C.
      Clinical significance of circulating vascular cell adhesion molecule-1 to white matter disintegrity in Alzheimer's dementia.
      • Donahue J.E.
      • Flaherty S.L.
      • Johanson C.E.
      • Duncan J.A.
      • Silverberg G.D.
      • Miller M.C.
      • Tavares R.
      • Yang W.
      • Wu Q.
      • Sabo E.
      • Hovanesian V.
      • Stopa E.G.
      RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease.
      • Miller M.C.
      • Tavares R.
      • Johanson C.E.
      • Hovanesian V.
      • Donahue J.E.
      • Gonzalez L.
      • Silverberg G.D.
      • Stopa E.G.
      Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease.
      • Ihara M.
      • Polvikoski T.M.
      • Hall R.
      • Slade J.Y.
      • Perry R.H.
      • Oakley A.E.
      • Englund E.
      • O'Brien J.T.
      • Ince P.G.
      • Kalaria R.N.
      Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies.
      • Rajani R.M.
      • Quick S.
      • Ruigrok S.R.
      • Graham D.
      • Harris S.E.
      • Verhaaren B.F.J.
      • Fornage M.
      • Seshadri S.
      • Atanur S.S.
      • Dominiczak A.F.
      • Smith C.
      • Wardlaw J.M.
      • Williams A.
      Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats.
      • Shi Y.
      • Thrippleton M.J.
      • Makin S.D.
      • Marshall I.
      • Geerlings M.I.
      • de Craen A.J.M.
      • van Buchem M.A.
      • Wardlaw J.M.
      Cerebral blood flow in small vessel disease: a systematic review and meta-analysis.
      • Wardlaw J.M.
      • Sandercock P.A.
      • Dennis M.S.
      • Starr J.
      Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?.
      • Rasmussen I.J.
      • Tybjærg-Hansen A.
      • Rasmussen K.L.
      • Nordestgaard B.G.
      • Frikke-Schmidt R.
      Blood-brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals.
      • Nahirney P.C.
      • Reeson P.
      • Brown C.E.
      Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.
      • Knowland D.
      • Arac A.
      • Sekiguchi K.J.
      • Hsu M.
      • Lutz S.E.
      • Perrino J.
      • Steinberg G.K.
      • Barres B.A.
      • Nimmerjahn A.
      • Agalliu D.
      Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke.
      • Armulik A.
      • Genové G.
      • Mäe M.
      • Nisancioglu M.H.
      • Wallgard E.
      • Niaudet C.
      • He L.
      • Norlin J.
      • Lindblom P.
      • Strittmatter K.
      • Johansson B.R.
      • Betsholtz C.
      Pericytes regulate the blood-brain barrier.
      • Hassan A.
      • Gormley K.
      • O'Sullivan M.
      • Knight J.
      • Sham P.
      • Vallance P.
      • Bamford J.
      • Markus H.
      Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease.
      • Barker R.
      • Ashby E.L.
      • Wellington D.
      • Barrow V.M.
      • Palmer J.C.
      • Kehoe P.G.
      • Esiri M.M.
      • Love S.
      Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia.
      • Luo J.
      • Grammas P.
      Endothelin-1 is elevated in Alzheimer's disease brain microvessels and is neuroprotective.
      • Kelleher J.
      • Dickinson A.
      • Cain S.
      • Hu Y.
      • Bates N.
      • Harvey A.
      • Ren J.
      • Zhang W.
      • Moreton F.C.
      • Muir K.W.
      • Ward C.
      • Touyz R.M.
      • Sharma P.
      • Xu Q.
      • Kimber S.J.
      • Wang T.
      Patient-specific iPSC model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures.
      • Ruitenberg A.
      • den Heijer T.
      • Bakker S.L.
      • van Swieten J.C.
      • Koudstaal P.J.
      • Hofman A.
      • Breteler M.M.
      Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam study.
      • Liu J.
      • Jin X.
      • Liu K.J.
      • Liu W.
      Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage.
      • Bailey E.L.
      • Wardlaw J.M.
      • Graham D.
      • Dominiczak A.F.
      • Sudlow C.L.
      • Smith C.
      Cerebral small vessel endothelial structural changes predate hypertension in stroke-prone spontaneously hypertensive rats: a blinded, controlled immunohistochemical study of 5- to 21-week-old rats.
      • Lindahl P.
      • Johansson B.R.
      • Levéen P.
      • Betsholtz C.
      Pericyte loss and microaneurysm formation in PDGF-B-deficient mice.
      • Maisonpierre P.C.
      • Suri C.
      • Jones P.F.
      • Bartunkova S.
      • Wiegand S.J.
      • Radziejewski C.
      • Compton D.
      • McClain J.
      • Aldrich T.H.
      • Papadopoulos N.
      • Daly T.J.
      • Davis S.
      • Sato T.N.
      • Yancopoulos G.D.
      Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.
      For example, a large autopsy study found that 79.9% of patients have vascular pathologic signs.
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      In addition, genome-wide association studies found a large number of AD-related genes in vascular cells.
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      Evidence of BBB disruption has been found in postmortem tissue from patients with AD and cSVD.
      • McAleese K.E.
      • Graham S.
      • Dey M.
      • Walker L.
      • Erskine D.
      • Johnson M.
      • Johnston E.
      • Thomas A.J.
      • McKeith I.G.
      • DeCarli C.
      • Attems J.
      Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer's disease.
      ,
      • Halliday M.R.
      • Rege S.V.
      • Ma Q.
      • Zhao Z.
      • Miller C.A.
      • Winkler E.A.
      • Zlokovic B.V.
      Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease.
      In particular, patients with AD and APOE4 have increased deposition of the blood component fibrin(ogen) perivascularly,
      • Halliday M.R.
      • Rege S.V.
      • Ma Q.
      • Zhao Z.
      • Miller C.A.
      • Winkler E.A.
      • Zlokovic B.V.
      Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease.
      suggestive of leakage.
      Table 1Evidence of Vascular Pathologic Findings and Crossover in cSVD and AD
      FindingsClinicalPreclinical models
      cSVDADcSVDAD
      Amyloid plaques in tissue and cellsNo evidenceEvidence
      • Rosenberg G.A.
      Neurological diseases in relation to the blood-brain barrier.
      ,
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • Thal D.
      • Ghebremedhin E.
      • Orantes M.
      • Wiestler O.
      Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline.
      No evidenceEvidence
      • Sagare A.P.
      • Bell R.D.
      • Zhao Z.
      • Ma Q.
      • Winkler E.A.
      • Ramanathan A.
      • Zlokovic B.V.
      Pericyte loss influences Alzheimer-like neurodegeneration in mice.
      Angiogenic changes and markers (VEGF and TGF-β)
       Tissue and cellsEvidence
      • Tayler H.
      • Miners J.S.
      • Güzel Ö.
      • MacLachlan R.
      • Love S.
      Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.
      Evidence
      • Tayler H.
      • Miners J.S.
      • Güzel Ö.
      • MacLachlan R.
      • Love S.
      Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.
      ,
      • Vagnucci Jr., A.H.
      • Li W.W.
      Alzheimer's disease and angiogenesis.
      ,
      • Desai B.S.
      • Schneider J.A.
      • Li J.L.
      • Carvey P.M.
      • Hendey B.
      Evidence of angiogenic vessels in Alzheimer's disease.
      UnknownUnknown
       BiofluidsEvidence
      • Tarkowski E.
      • Issa R.
      • Sjögren M.
      • Wallin A.
      • Blennow K.
      • Tarkowski A.
      • Kumar P.
      Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer's disease and vascular dementia.
      Evidence
      • Tarkowski E.
      • Issa R.
      • Sjögren M.
      • Wallin A.
      • Blennow K.
      • Tarkowski A.
      • Kumar P.
      Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer's disease and vascular dementia.
      UnknownUnknown
      BBB leakage [fibrin(ogen), IgG, tracer, albumin, ANGPT2]
       Tissue and cellsEvidence
      • McAleese K.E.
      • Graham S.
      • Dey M.
      • Walker L.
      • Erskine D.
      • Johnson M.
      • Johnston E.
      • Thomas A.J.
      • McKeith I.G.
      • DeCarli C.
      • Attems J.
      Extravascular fibrinogen in the white matter of Alzheimer's disease and normal aged brains: implications for fibrinogen as a biomarker for Alzheimer's disease.
      ,
      • Rajani R.M.
      • Ratelade J.
      • Domenga-Denier V.
      • Hase Y.
      • Kalimo H.
      • Kalaria R.N.
      • Joutel A.
      Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.
      ,
      • Grinberg L.
      • Thal D.
      Vascular pathology in the aged human brain.
      Evidence
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • Tayler H.
      • Miners J.S.
      • Güzel Ö.
      • MacLachlan R.
      • Love S.
      Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer's disease, vascular dementia and mixed dementia.
      ,
      • Halliday M.R.
      • Rege S.V.
      • Ma Q.
      • Zhao Z.
      • Miller C.A.
      • Winkler E.A.
      • Zlokovic B.V.
      Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease.
      ,
      • Sengillo J.D.
      • Winkler E.A.
      • Walker C.T.
      • Sullivan J.S.
      • Johnson M.
      • Zlokovic B.V.
      Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease.
      Evidence
      • Sironi L.
      • Guerrini U.
      • Tremoli E.
      • Miller I.
      • Gelosa P.
      • Lascialfari A.
      • Zucca I.
      • Eberini I.
      • Gemeiner M.
      • Paoletti R.
      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      ,
      • Schreiber S.
      • Bueche C.Z.
      • Garz C.
      • Kropf S.
      • Angenstein F.
      • Goldschmidt J.
      • Neumann J.
      • Heinze H.J.
      • Goertler M.
      • Reymann K.G.
      • Braun H.
      The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase?.
      Evidence
      • Nikolakopoulou A.M.
      • Montagne A.
      • Kisler K.
      • Dai Z.
      • Wang Y.
      • Huuskonen M.T.
      • Sagare A.P.
      • Lazic D.
      • Sweeney M.D.
      • Kong P.
      • Wang M.
      • Owens N.C.
      • Lawson E.J.
      • Xie X.
      • Zhao Z.
      • Zlokovic B.V.
      Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.
      ,
      • Sweeney M.D.
      • Kisler K.
      • Montagne A.
      • Toga A.W.
      • Zlokovic B.V.
      The role of brain vasculature in neurodegenerative disorders.
      ,
      • Bell R.D.
      • Winkler E.A.
      • Sagare A.P.
      • Singh I.
      • LaRue B.
      • Deane R.
      • Zlokovic B.V.
      Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.
      ,
      • Montagne A.
      • Nikolakopoulou A.M.
      • Zhao Z.
      • Sagare A.P.
      • Si G.
      • Lazic D.
      • Barnes S.R.
      • Daianu M.
      • Ramanathan A.
      • Go A.
      • Lawson E.J.
      • Wang Y.
      • Mack W.J.
      • Thompson P.M.
      • Schneider J.A.
      • Varkey J.
      • Langen R.
      • Mullins E.
      • Jacobs R.E.
      • Zlokovic B.V.
      Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.
      ,
      • Mäe M.A.
      • He L.
      • Nordling S.
      • Vazquez-Liebanas E.
      • Nahar K.
      • Jung B.
      • Li X.
      • Tan B.C.
      • Chin Foo J.
      • Cazenave-Gassiot A.
      • Wenk M.R.
      • Zarb Y.
      • Lavina B.
      • Quaggin S.E.
      • Jeansson M.
      • Gu C.
      • Silver D.L.
      • Vanlandewijck M.
      • Butcher E.C.
      • Keller A.
      • Betsholtz C.
      Single-cell analysis of blood-brain barrier response to pericyte loss.
      ,
      • Nikolakopoulou A.M.
      • Wang Y.
      • Ma Q.
      • Sagare A.P.
      • Montagne A.
      • Huuskonen M.T.
      • Rege S.V.
      • Kisler K.
      • Dai Z.
      • Körbelin J.
      • Herz J.
      • Zhao Z.
      • Zlokovic B.V.
      Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A.
       BiofluidsUnknownEvidence
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • Raman M.R.
      • Himali J.J.
      • Conner S.C.
      • DeCarli C.
      • Vasan R.S.
      • Beiser A.S.
      • Seshadri S.
      • Maillard P.
      • Satizabal C.L.
      Circulating vascular growth factors and magnetic resonance imaging markers of small vessel disease and atrophy in middle-aged adults.
      Evidence
      • Sironi L.
      • Guerrini U.
      • Tremoli E.
      • Miller I.
      • Gelosa P.
      • Lascialfari A.
      • Zucca I.
      • Eberini I.
      • Gemeiner M.
      • Paoletti R.
      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      Unknown
       NeuroimagingEvidence
      • Rosenberg G.A.
      Neurological diseases in relation to the blood-brain barrier.
      ,
      • Wardlaw J.M.
      • Makin S.J.
      • Valdés Hernández M.C.
      • Armitage P.A.
      • Heye A.K.
      • Chappell F.M.
      • Muñoz-Maniega S.
      • Sakka E.
      • Shuler K.
      • Dennis M.S.
      • Thrippleton M.J.
      Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study.
      ,
      • Zhang C.E.
      • Wong S.M.
      • Uiterwijk R.
      • Backes W.H.
      • Jansen J.F.A.
      • Jeukens C.
      • van Oostenbrugge R.J.
      • Staals J.
      Blood-brain barrier leakage in relation to white matter hyperintensity volume and cognition in small vessel disease and normal aging.
      Evidence
      • Rosenberg G.A.
      Neurological diseases in relation to the blood-brain barrier.
      ,
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • van de Haar H.J.
      • Jansen J.F.A.
      • van Osch M.J.P.
      • van Buchem M.A.
      • Muller M.
      • Wong S.M.
      • Hofman P.A.M.
      • Burgmans S.
      • Verhey F.R.J.
      • Backes W.H.
      Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging.
      ,
      • Montagne A.
      • Barnes S.R.
      • Sweeney M.D.
      • Halliday M.R.
      • Sagare A.P.
      • Zhao Z.
      • Toga A.W.
      • Jacobs R.E.
      • Liu C.Y.
      • Amezcua L.
      • Harrington M.G.
      • Chui H.C.
      • Law M.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in the aging human hippocampus.
      ,
      • Montagne A.
      • Nation D.A.
      • Sagare A.P.
      • Barisano G.
      • Sweeney M.D.
      • Chakhoyan A.
      • Pachicano M.
      • Joe E.
      • Nelson A.R.
      • D'Orazio L.M.
      • Buennagel D.P.
      • Harrington M.G.
      • Benzinger T.L.S.
      • Fagan A.M.
      • Ringman J.M.
      • Schneider L.S.
      • Morris J.C.
      • Reiman E.M.
      • Caselli R.J.
      • Chui H.C.
      • Tcw J.
      • Chen Y.
      • Pa J.
      • Conti P.S.
      • Law M.
      • Toga A.W.
      • Zlokovic B.V.
      APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
      Evidence
      • Sironi L.
      • Guerrini U.
      • Tremoli E.
      • Miller I.
      • Gelosa P.
      • Lascialfari A.
      • Zucca I.
      • Eberini I.
      • Gemeiner M.
      • Paoletti R.
      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      ,
      • Schreiber S.
      • Bueche C.Z.
      • Garz C.
      • Braun H.
      Blood brain barrier breakdown as the starting point of cerebral small vessel disease?: new insights from a rat model.
      Evidence
      • Nikolakopoulou A.M.
      • Wang Y.
      • Ma Q.
      • Sagare A.P.
      • Montagne A.
      • Huuskonen M.T.
      • Rege S.V.
      • Kisler K.
      • Dai Z.
      • Körbelin J.
      • Herz J.
      • Zhao Z.
      • Zlokovic B.V.
      Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A.
      Enlarged PVS in tissue and cellsEvidence
      • Rajani R.M.
      • Ratelade J.
      • Domenga-Denier V.
      • Hase Y.
      • Kalimo H.
      • Kalaria R.N.
      • Joutel A.
      Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.
      No evidenceUnknownNo evidence
      Infarcts
       Tissue and cellsEvidence
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      Evidence
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      Evidence
      • Schreiber S.
      • Bueche C.Z.
      • Garz C.
      • Braun H.
      Blood brain barrier breakdown as the starting point of cerebral small vessel disease?: new insights from a rat model.
      Unknown
       NeuroimagingEvidence
      • Rosenberg G.A.
      Neurological diseases in relation to the blood-brain barrier.
      ,
      • Toledo J.B.
      • Arnold S.E.
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      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      Evidence
      • Liu Y.
      • Braidy N.
      • Poljak A.
      • Chan D.K.Y.
      • Sachdev P.
      Cerebral small vessel disease and the risk of Alzheimer's disease: a systematic review.
      UnknownUnknown
      Lacunes in tissue and cellsEvidence
      • Rajani R.M.
      • Ratelade J.
      • Domenga-Denier V.
      • Hase Y.
      • Kalimo H.
      • Kalaria R.N.
      • Joutel A.
      Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.
      ,
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      Evidence
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      UnknownUnknown
      Microbleeds
       Tissue and cellsEvidence
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      Evidence
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      Evidence
      • Schreiber S.
      • Bueche C.Z.
      • Garz C.
      • Braun H.
      Blood brain barrier breakdown as the starting point of cerebral small vessel disease?: new insights from a rat model.
      Evidence
      • Hellström M.
      • Gerhardt H.
      • Kalén M.
      • Li X.
      • Eriksson U.
      • Wolburg H.
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      Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis.
       NeuroimagingEvidence
      • Patel B.
      • Lawrence A.J.
      • Chung A.W.
      • Rich P.
      • Mackinnon A.D.
      • Morris R.G.
      • Barrick T.R.
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      Cerebral microbleeds and cognition in patients with symptomatic small vessel disease.
      Evidence
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      ,
      • Cordonnier C.
      • van der Flier W.M.
      Brain microbleeds and Alzheimer's disease: innocent observation or key player?.
      UnknownUnknown
      Neuroinflammation (MMPs, CAMs, CypA, and RAGE)
       Tissue and cellsUnknownEvidence
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      ,
      • Halliday M.R.
      • Rege S.V.
      • Ma Q.
      • Zhao Z.
      • Miller C.A.
      • Winkler E.A.
      • Zlokovic B.V.
      Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease.
      ,
      • Verbeek M.M.
      • Otte-Höller I.
      • Westphal J.R.
      • Wesseling P.
      • Ruiter D.J.
      • de Waal R.M.
      Accumulation of intercellular adhesion molecule-1 in senile plaques in brain tissue of patients with Alzheimer's disease.
      Evidence
      • Bailey E.L.
      • McBride M.W.
      • Beattie W.
      • McClure J.D.
      • Graham D.
      • Dominiczak A.F.
      • Sudlow C.L.
      • Smith C.
      • Wardlaw J.M.
      Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.
      Evidence
      • Bell R.D.
      • Winkler E.A.
      • Sagare A.P.
      • Singh I.
      • LaRue B.
      • Deane R.
      • Zlokovic B.V.
      Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.
      ,
      • Mäe M.A.
      • He L.
      • Nordling S.
      • Vazquez-Liebanas E.
      • Nahar K.
      • Jung B.
      • Li X.
      • Tan B.C.
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      Single-cell analysis of blood-brain barrier response to pericyte loss.
      ,
      • Nikolakopoulou A.M.
      • Wang Y.
      • Ma Q.
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      • Montagne A.
      • Huuskonen M.T.
      • Rege S.V.
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      • Herz J.
      • Zhao Z.
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      Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A.
      ,
      • Blanchard J.W.
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      • Cam H.P.
      • Kellis M.
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      Reconstruction of the human blood-brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes.
      ,
      • Török O.
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      • Tsai H.C.
      • Maheshwari U.
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      Pericytes regulate vascular immune homeostasis in the CNS.
      ,
      • Daneman R.
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      • Kebede A.A.
      • Barres B.A.
      Pericytes are required for blood-brain barrier integrity during embryogenesis.
       BiofluidsEvidence
      • Rouhl R.P.
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      • Kroon A.A.
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      Vascular inflammation in cerebral small vessel disease.
      ,
      • Kim Y.
      • Kim Y.K.
      • Kim N.K.
      • Kim S.H.
      • Kim O.J.
      • Oh S.H.
      Circulating matrix metalloproteinase-9 level is associated with cerebral white matter hyperintensities in non-stroke individuals.
      Evidence
      • Halliday M.R.
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      • Ma Q.
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      • Miller C.A.
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      Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer's disease.
      ,
      • Montagne A.
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      • Sagare A.P.
      • Barisano G.
      • Sweeney M.D.
      • Chakhoyan A.
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      • Pa J.
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      • Law M.
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      APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
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      • Huang C.W.
      • Tsai M.H.
      • Chen N.C.
      • Chen W.H.
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      • Lui C.C.
      • Chang Y.T.
      • Chang W.N.
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      Clinical significance of circulating vascular cell adhesion molecule-1 to white matter disintegrity in Alzheimer's dementia.
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      • Donahue J.E.
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      RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease.
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      • Miller M.C.
      • Tavares R.
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      • Hovanesian V.
      • Donahue J.E.
      • Gonzalez L.
      • Silverberg G.D.
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      Hippocampal RAGE immunoreactivity in early and advanced Alzheimer's disease.
      Evidence
      • Sironi L.
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      • Miller I.
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      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      Unknown
      Parenchymal changes and WMHs (myelin loss, gliosis, and neuronal loss)
       Tissue and cellsEvidence
      • Rajani R.M.
      • Ratelade J.
      • Domenga-Denier V.
      • Hase Y.
      • Kalimo H.
      • Kalaria R.N.
      • Joutel A.
      Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.
      ,
      • Ihara M.
      • Polvikoski T.M.
      • Hall R.
      • Slade J.Y.
      • Perry R.H.
      • Oakley A.E.
      • Englund E.
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      • Ince P.G.
      • Kalaria R.N.
      Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies.
      Evidence
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • Thal D.
      • Ghebremedhin E.
      • Orantes M.
      • Wiestler O.
      Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline.
      Evidence
      • Sironi L.
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      • Miller I.
      • Gelosa P.
      • Lascialfari A.
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      • Gemeiner M.
      • Paoletti R.
      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      ,
      • Bailey E.L.
      • McBride M.W.
      • Beattie W.
      • McClure J.D.
      • Graham D.
      • Dominiczak A.F.
      • Sudlow C.L.
      • Smith C.
      • Wardlaw J.M.
      Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.
      ,
      • Rajani R.M.
      • Quick S.
      • Ruigrok S.R.
      • Graham D.
      • Harris S.E.
      • Verhaaren B.F.J.
      • Fornage M.
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      • Atanur S.S.
      • Dominiczak A.F.
      • Smith C.
      • Wardlaw J.M.
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      Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats.
      Evidence
      • Montagne A.
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      • Zhao Z.
      • Sagare A.P.
      • Si G.
      • Lazic D.
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      • Ramanathan A.
      • Go A.
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      • Varkey J.
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      • Mullins E.
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      • Zlokovic B.V.
      Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.
      ,
      • Nikolakopoulou A.M.
      • Wang Y.
      • Ma Q.
      • Sagare A.P.
      • Montagne A.
      • Huuskonen M.T.
      • Rege S.V.
      • Kisler K.
      • Dai Z.
      • Körbelin J.
      • Herz J.
      • Zhao Z.
      • Zlokovic B.V.
      Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A.
       NeuroimagingEvidence
      • Rosenberg G.A.
      Neurological diseases in relation to the blood-brain barrier.
      ,
      • Wardlaw J.M.
      • Makin S.J.
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      • Armitage P.A.
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      Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study.
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      • Zhang C.E.
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      • Jeukens C.
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      • Staals J.
      Blood-brain barrier leakage in relation to white matter hyperintensity volume and cognition in small vessel disease and normal aging.
      ,
      • Rajani R.M.
      • Quick S.
      • Ruigrok S.R.
      • Graham D.
      • Harris S.E.
      • Verhaaren B.F.J.
      • Fornage M.
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      • Atanur S.S.
      • Dominiczak A.F.
      • Smith C.
      • Wardlaw J.M.
      • Williams A.
      Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats.
      ,
      • Shi Y.
      • Thrippleton M.J.
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      • Marshall I.
      • Geerlings M.I.
      • de Craen A.J.M.
      • van Buchem M.A.
      • Wardlaw J.M.
      Cerebral blood flow in small vessel disease: a systematic review and meta-analysis.
      Evidence
      • Liu Y.
      • Braidy N.
      • Poljak A.
      • Chan D.K.Y.
      • Sachdev P.
      Cerebral small vessel disease and the risk of Alzheimer's disease: a systematic review.
      ,
      • Wardlaw J.M.
      • Sandercock P.A.
      • Dennis M.S.
      • Starr J.
      Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia?.
      Evidence
      • Rajani R.M.
      • Ratelade J.
      • Domenga-Denier V.
      • Hase Y.
      • Kalimo H.
      • Kalaria R.N.
      • Joutel A.
      Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.
      ,
      • Sironi L.
      • Guerrini U.
      • Tremoli E.
      • Miller I.
      • Gelosa P.
      • Lascialfari A.
      • Zucca I.
      • Eberini I.
      • Gemeiner M.
      • Paoletti R.
      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      Unknown
      Pericyte loss (sPDGFR-β)
       Tissue and cellsUnknownEvidence
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      ,
      • Sengillo J.D.
      • Winkler E.A.
      • Walker C.T.
      • Sullivan J.S.
      • Johnson M.
      • Zlokovic B.V.
      Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease.
      ,
      • Montagne A.
      • Barnes S.R.
      • Sweeney M.D.
      • Halliday M.R.
      • Sagare A.P.
      • Zhao Z.
      • Toga A.W.
      • Jacobs R.E.
      • Liu C.Y.
      • Amezcua L.
      • Harrington M.G.
      • Chui H.C.
      • Law M.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in the aging human hippocampus.
      UnknownEvidence
      • Sagare A.P.
      • Bell R.D.
      • Zhao Z.
      • Ma Q.
      • Winkler E.A.
      • Ramanathan A.
      • Zlokovic B.V.
      Pericyte loss influences Alzheimer-like neurodegeneration in mice.
       BiofluidsUnknownEvidence
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      ,
      • Nelson A.R.
      • Sweeney M.D.
      • Sagare A.P.
      • Zlokovic B.V.
      Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
      ,
      • Montagne A.
      • Barnes S.R.
      • Sweeney M.D.
      • Halliday M.R.
      • Sagare A.P.
      • Zhao Z.
      • Toga A.W.
      • Jacobs R.E.
      • Liu C.Y.
      • Amezcua L.
      • Harrington M.G.
      • Chui H.C.
      • Law M.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in the aging human hippocampus.
      ,
      • Montagne A.
      • Nation D.A.
      • Sagare A.P.
      • Barisano G.
      • Sweeney M.D.
      • Chakhoyan A.
      • Pachicano M.
      • Joe E.
      • Nelson A.R.
      • D'Orazio L.M.
      • Buennagel D.P.
      • Harrington M.G.
      • Benzinger T.L.S.
      • Fagan A.M.
      • Ringman J.M.
      • Schneider L.S.
      • Morris J.C.
      • Reiman E.M.
      • Caselli R.J.
      • Chui H.C.
      • Tcw J.
      • Chen Y.
      • Pa J.
      • Conti P.S.
      • Law M.
      • Toga A.W.
      • Zlokovic B.V.
      APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
      UnknownUnknown
      Transcytosis in tissue and cellsEvidence
      • Rasmussen I.J.
      • Tybjærg-Hansen A.
      • Rasmussen K.L.
      • Nordestgaard B.G.
      • Frikke-Schmidt R.
      Blood-brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals.
      Evidence
      • Rasmussen I.J.
      • Tybjærg-Hansen A.
      • Rasmussen K.L.
      • Nordestgaard B.G.
      • Frikke-Schmidt R.
      Blood-brain barrier transcytosis genes, risk of dementia and stroke: a prospective cohort study of 74,754 individuals.
      Evidence
      • Nahirney P.C.
      • Reeson P.
      • Brown C.E.
      Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.
      ,
      • Knowland D.
      • Arac A.
      • Sekiguchi K.J.
      • Hsu M.
      • Lutz S.E.
      • Perrino J.
      • Steinberg G.K.
      • Barres B.A.
      • Nimmerjahn A.
      • Agalliu D.
      Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke.
      Evidence
      • Daneman R.
      • Zhou L.
      • Kebede A.A.
      • Barres B.A.
      Pericytes are required for blood-brain barrier integrity during embryogenesis.
      ,
      • Armulik A.
      • Genové G.
      • Mäe M.
      • Nisancioglu M.H.
      • Wallgard E.
      • Niaudet C.
      • He L.
      • Norlin J.
      • Lindblom P.
      • Strittmatter K.
      • Johansson B.R.
      • Betsholtz C.
      Pericytes regulate the blood-brain barrier.
      Vasoactive dysregulation and CBF (NO and ET-1)
       Tissue and cellsEvidence
      • Hassan A.
      • Gormley K.
      • O'Sullivan M.
      • Knight J.
      • Sham P.
      • Vallance P.
      • Bamford J.
      • Markus H.
      Endothelial nitric oxide gene haplotypes and risk of cerebral small-vessel disease.
      Evidence
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      ,
      • Barker R.
      • Ashby E.L.
      • Wellington D.
      • Barrow V.M.
      • Palmer J.C.
      • Kehoe P.G.
      • Esiri M.M.
      • Love S.
      Pathophysiology of white matter perfusion in Alzheimer's disease and vascular dementia.
      ,
      • Luo J.
      • Grammas P.
      Endothelin-1 is elevated in Alzheimer's disease brain microvessels and is neuroprotective.
      Evidence
      • Rajani R.M.
      • Quick S.
      • Ruigrok S.R.
      • Graham D.
      • Harris S.E.
      • Verhaaren B.F.J.
      • Fornage M.
      • Seshadri S.
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      Examples from selected references of neuropathology are seen in tissue and biofluids, such as serum and cerebrospinal fluid, as well as on neuroimaging, such as magnetic resonance imaging.
      AD, Alzheimer disease; ANGPT2, angiopoietin-2; CAMs, cellular adhesion molecules; CBF, cerebral blood flow; cSVD, cerebral small vessel disease; CypA, cyclophilin A; ET-1, endothelin-1; MMPs, matrix metalloproteinases; NO, nitric oxide; RAGE, receptor for advanced glycation end products; sPDGFR-β, soluble platelet-derived growth factor receptor β; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor; WMHs, white matter hyperintensities.
      Clinical diagnosis of AD or cSVD is supported through visualization of changes on magnetic resonance imaging (MRI) (Table 1), with BBB leakage detectable with dynamic contrast-enhanced MRI, and intravenous injection of gadolinium-based tracers. Gadolinium tracer leakage is seen in AD,
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      originate, to a large degree, from the disruption of the BBB.
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      In patients with cSVD, occurrence of BBB breakdown in WMHs is indicated by increased gadolinium leakage compared with that in the surrounding normal-appearing white matter,
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      Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study.
      and the degree of BBB breakdown positively correlates with WMH volume.
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      and demonstrating the importance of BBB breakdown as a core pathologic mechanism in dementia. Of interest, BBB leakage in the hippocampus of patients with mild cognitive impairment correlates with cerebrospinal fluid (CSF) levels of soluble PDGFR-β,
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      APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline.
      a marker of damaged pericytes,
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      which prompts further consideration of their role in dementia.

      Loss of Pericyte-Endothelial Signaling and BBB Breakdown

      Pericytes directly encircle endothelial cells, and their vascular coverage is thought to positively correlate with barrier strength.
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      Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability.
      There is much debate about the extent of cerebral pericyte-endothelial cell coverage, primarily because of the wide variety of ways of measuring it. Some studies use electron microscopy to define coverage as a percentage of endothelial cell encircled by pericytes,
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      Pericyte coverage of retinal and cerebral capillaries.
      although more recent studies use PDGFR-β immunofluorescence to define coverage as a percentage of the vessel area that is PDGFR-β-positive and assess the number of pericytes by counting PDGFR-β–positive cell bodies.
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      Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability.
      In addition, it is likely that coverage varies between organ and tissue location within the organ.
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      A study of retinal and brain cortical tissue found that pericytes covered 85% of the capillary circumference in human and monkey retinas, but coverage was significantly less in monkey cortex.
      • Frank R.N.
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      • Das A.
      Pericyte coverage of retinal and cerebral capillaries.
      This study used electron microscopy to determine the extent of pericyte coverage, thereby examining very small areas and perhaps not detecting variation between blood vessels in different regions. Pericytes cover up to 80% of brain capillaries in the human cortex and hippocampus, as indicated by immunofluorescence.
      • Sengillo J.D.
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      In three regions of mouse brain, coverage was approximately 80%, whereas in the spinal cord, pericyte coverage varied from 48% to 68%, depending on location.
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      Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability.
      Pericyte coverage is heterogeneous and dependent on subtype, which relates to vessel diameter, leading to variations in vessel coverage. In mice, ensheathing pericytes cover up to 95% of the vessel, whereas mesh and thin-strand pericytes cover 71% and 51%, respectively.
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      However, it is generally accepted that in the CNS a high proportion of endothelial cells are encircled by pericytes, hinting at the vital role they play in the NVU and regulation of the BBB,
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      Blood-spinal cord barrier pericyte reductions contribute to increased capillary permeability.
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      Pericytes: developmental, physiological, and pathological perspectives, problems, and promises.
      but the exact figures vary among species, brain regions, and measurement techniques. Of importance, pericyte coverage appears to be related to BBB leakage because naturally leaky capillaries of the ME have a reduced pericyte coverage in mice compared with cortical capillaries.
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      • Montagne A.
      • Barnes S.R.
      • Sweeney M.D.
      • Halliday M.R.
      • Sagare A.P.
      • Zhao Z.
      • Toga A.W.
      • Jacobs R.E.
      • Liu C.Y.
      • Amezcua L.
      • Harrington M.G.
      • Chui H.C.
      • Law M.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in the aging human hippocampus.
      which correlates with worse cognitive impairment.
      • Montagne A.
      • Barnes S.R.
      • Sweeney M.D.
      • Halliday M.R.
      • Sagare A.P.
      • Zhao Z.
      • Toga A.W.
      • Jacobs R.E.
      • Liu C.Y.
      • Amezcua L.
      • Harrington M.G.
      • Chui H.C.
      • Law M.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in the aging human hippocampus.
      Loss of pericytes in disease appears greater than that of in normal aging,
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      ,
      • Sengillo J.D.
      • Winkler E.A.
      • Walker C.T.
      • Sullivan J.S.
      • Johnson M.
      • Zlokovic B.V.
      Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease.
      with patients with AD having up to a 60% reduction in pericyte number and 30% reduction in capillary coverage when compared with controls, as indicated by PDGFR-β immunostaining.
      • Sengillo J.D.
      • Winkler E.A.
      • Walker C.T.
      • Sullivan J.S.
      • Johnson M.
      • Zlokovic B.V.
      Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease.
      Furthermore, a recent study found an overall reduction in VMCs and endothelial cells in patients with AD, in particular a subtype of pericytes involved in regulating the ECM.
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      The loss of pericytes may occur through disruption of the endothelial sphingosine-1-phosphate (S1P) receptor, which is involved in regulating pericyte vessel coverage
      • Paik J.H.
      • Skoura A.
      • Chae S.S.
      • Cowan A.E.
      • Han D.K.
      • Proia R.L.
      • Hla T.
      Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization.
      ,
      • Allende M.L.
      • Yamashita T.
      • Proia R.L.
      G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation.
      by controlling N-cadherin trafficking to the membrane needed for endothelial-pericyte adhesion. A reduction in S1P receptors occurs in AD brain tissue,
      • Ceccom J.
      • Loukh N.
      • Lauwers-Cances V.
      • Touriol C.
      • Nicaise Y.
      • Gentil C.
      • Uro-Coste E.
      • Pitson S.
      • Maurage C.A.
      • Duyckaerts C.
      • Cuvillier O.
      • Delisle M.B.
      Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease.
      and an S1P analogue, a ligand for the S1P receptor, reduces memory impairment in an AD mouse model.
      • Asle-Rousta M.
      • Kolahdooz Z.
      • Dargahi L.
      • Ahmadiani A.
      • Nasoohi S.
      Prominence of central sphingosine-1-phosphate receptor-1 in attenuating aβ-induced injury by fingolimod.
      The neuroprotective effect of S1P is mediated by reducing amyloid-β (Aβ)–induced neuronal apoptosis
      • Malaplate-Armand C.
      • Florent-Béchard S.
      • Youssef I.
      • Koziel V.
      • Sponne I.
      • Kriem B.
      • Leininger-Muller B.
      • Olivier J.L.
      • Oster T.
      • Pillot T.
      Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway.
      and reducing levels of certain S1P isoforms in vascular dementia.
      • Chua X.Y.
      • Chai Y.L.
      • Chew W.S.
      • Chong J.R.
      • Ang H.L.
      • Xiang P.
      • Camara K.
      • Howell A.R.
      • Torta F.
      • Wenk M.R.
      • Hilal S.
      • Venketasubramanian N.
      • Chen C.P.
      • Herr D.R.
      • Lai M.K.P.
      Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer's disease and vascular cognitive impairment.
      In addition, dysregulation of S1P is implicated in neuroinflammation,
      • Chua X.Y.
      • Chai Y.L.
      • Chew W.S.
      • Chong J.R.
      • Ang H.L.
      • Xiang P.
      • Camara K.
      • Howell A.R.
      • Torta F.
      • Wenk M.R.
      • Hilal S.
      • Venketasubramanian N.
      • Chen C.P.
      • Herr D.R.
      • Lai M.K.P.
      Immunomodulatory sphingosine-1-phosphates as plasma biomarkers of Alzheimer's disease and vascular cognitive impairment.
      another pathophysiologic component of AD and cSVD.
      • Fu Y.
      • Yan Y.
      Emerging role of immunity in cerebral small vessel disease.
      Therefore, S1P and S1P receptor play a role in the pathophysiologic mechanisms of dementia by altering amyloid-induced apoptosis, neuroinflammation, and endothelial-pericyte adhesion.
      Interestingly, recent evidence from a genetic form of vascular dementia, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), has found no reduced pericyte coverage in patients or a mouse model.
      • Rajani R.M.
      • Ratelade J.
      • Domenga-Denier V.
      • Hase Y.
      • Kalimo H.
      • Kalaria R.N.
      • Joutel A.
      Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.
      These patients harbor mutations in the NOTCH3 gene; therefore, the BBB disruption seen may be attributable to the requirement of NOTCH for adhesion of endothelial cells and VSMCs to the basement membrane, affecting vessel stability.
      • Scheppke L.
      • Murphy E.A.
      • Zarpellon A.
      • Hofmann J.J.
      • Merkulova A.
      • Shields D.J.
      • Weis S.M.
      • Byzova T.V.
      • Ruggeri Z.M.
      • Iruela-Arispe M.L.
      • Cheresh D.A.
      Notch promotes vascular maturation by inducing integrin-mediated smooth muscle cell adhesion to the endothelial basement membrane.
      In addition, pluripotent stem cell (iPSC)–derived VMCs in patients with CADASIL have reduced PDGFR-β and can induce apoptosis in neighboring endothelial cells, leading to decreased blood vessel stability. This phenotype is specific to the vascular mural iPSCs because the endothelial iPSCs are able to form normal vessel networks.
      • Kelleher J.
      • Dickinson A.
      • Cain S.
      • Hu Y.
      • Bates N.
      • Harvey A.
      • Ren J.
      • Zhang W.
      • Moreton F.C.
      • Muir K.W.
      • Ward C.
      • Touyz R.M.
      • Sharma P.
      • Xu Q.
      • Kimber S.J.
      • Wang T.
      Patient-specific iPSC model of a genetic vascular dementia syndrome reveals failure of mural cells to stabilize capillary structures.
      Furthermore, differentially expressed genes in the VMCs of patients with AD are similar to those seen in CADASIL, and ECM maintenance in AD involves loss of a pericyte subtype.
      • Yang A.C.
      • Vest R.T.
      • Kern F.
      • Lee D.
      • Maat C.A.
      • Losada P.M.
      • Chen M.B.
      • Agam M.
      • Schaum N.
      • Khoury N.
      • Calcuttawala K.
      • Palovics R.
      • Shin A.
      • Wang E.Y.
      • Luo J.
      • Gate D.
      • Siegenthaler J.A.
      • McNerney M.W.
      • Keller A.
      • Wyss-Coray T.
      A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk.
      Together, these data suggest that BBB disruption in dementia occurs not only through loss of pericyte coverage and endothelial-pericyte contact but also through ECM disruption and/or loss of PDGFR-β signaling (Figure 2).
      Figure thumbnail gr2
      Figure 2Loss of pericyte-endothelial crosstalk in cerebral small vessel disease and Alzheimer disease. Disruption to endothelial-pericyte signaling leads to a wide variety of changes: (1) pericyte loss; (2) endothelial cell activation and extravasation of immune cells; (3) loss of balanced amyloid-β (Aβ) transport caused by increased receptor for advanced glycation end products and loss of low-density lipoprotein receptor–related protein 1 (LRP1), leading to Aβ build-up in the brain; (4) loss of LRP1 also contributes to loss of inhibition of the cyclophilin A–matrix metalloproteinase (MMP)-9 pathway, leading to extracellular matrix/basement membrane breakdown by MMPs; (5) MMP activation contributes to loss of junctional proteins, changes in organization, and widening junctional gap between endothelial cells; (6) transcriptional changes that lead to a more venous phenotype; (7) reduced major facilitator superfamily domain containing 2a, which contributes to increased transcytosis; (8) BBB breakdown and ingress of neurotoxic substances such as fibrin(ogen) into the brain; (9) dysregulation of vasoactive substances (eg, nitric oxide) and subsequent reduced cerebral blood flow (CBF); and (10) morphologic changes to endothelial cells with cellular hyperplasia and aberrant angiogenesis. Figure generated with Biorender.com (Biorender, Toronto, Ontario, Canada). CAMs, cellular adhesion molecules; CLDN-5, claudin-5; ICAM-1, intercellular adhesion molecule 1; PDGFR-β, platelet-derived growth factor receptor β; PLVAP, plasmalemma vesicle–associated protein; VCAM-1, vascular cell adhesion molecule 1; ZO-1, zonula occludens protein 1.
      Platelet-derived growth factor β (PDGF-β)/PDGFR-β signaling is one of the most studied and important pathways in pericyte-endothelial crosstalk. Brain endothelial cells are enriched for and secrete PDGF-β,
      • Daneman R.
      • Zhou L.
      • Agalliu D.
      • Cahoy J.D.
      • Kaushal A.
      • Barres B.A.
      The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells.
      which binds to pericyte-specific PDGFR-β.
      • Winkler E.A.
      • Bell R.D.
      • Zlokovic B.V.
      Pericyte-specific expression of PDGF beta receptor in mouse models with normal and deficient PDGF beta receptor signaling.
      Most knowledge of the PDGF-β/PDGFR-β signaling pathway stems from studying Pdgfb- or Pdgfrb-null embryos (because these mice do not survive to birth
      • Hellström M.
      • Gerhardt H.
      • Kalén M.
      • Li X.
      • Eriksson U.
      • Wolburg H.
      • Betsholtz C.
      Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis.
      ) or postnatally in hypomorphic Pdgfbret/ret- or Pdgfrb-deficient models. Of importance, these models have helped further the understanding of possible mechanisms that contribute to BBB breakdown seen in cSVD and AD.
      • Wardlaw J.M.
      • Makin S.J.
      • Valdés Hernández M.C.
      • Armitage P.A.
      • Heye A.K.
      • Chappell F.M.
      • Muñoz-Maniega S.
      • Sakka E.
      • Shuler K.
      • Dennis M.S.
      • Thrippleton M.J.
      Blood-brain barrier failure as a core mechanism in cerebral small vessel disease and dementia: evidence from a cohort study.
      ,
      • Toledo J.B.
      • Arnold S.E.
      • Raible K.
      • Brettschneider J.
      • Xie S.X.
      • Grossman M.
      • Monsell S.E.
      • Kukull W.A.
      • Trojanowski J.Q.
      Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer's Coordinating Centre.
      As mentioned above, clinical data from patients with dementia indicate an increase in soluble PDGFR-β in the CSF,
      • Montagne A.
      • Barnes S.R.
      • Sweeney M.D.
      • Halliday M.R.
      • Sagare A.P.
      • Zhao Z.
      • Toga A.W.
      • Jacobs R.E.
      • Liu C.Y.
      • Amezcua L.
      • Harrington M.G.
      • Chui H.C.
      • Law M.
      • Zlokovic B.V.
      Blood-brain barrier breakdown in the aging human hippocampus.
      supporting the involvement of PDGF-β/PDGFR-β signaling in disease pathology. Further evidence of the clinical importance of disruption to the PDGF-β/PDGFR-β signaling pathway can be seen after surgically-induced large vessel stroke in adult Pdgfrb knockout mice, which indicates reduced pericyte coverage, significantly larger stroke lesions, and more BBB leakage, as compared with controls. This phenotype is significantly rescued with the preservation of PDGFR-β expression in pericytes.
      • Shen J.
      • Ishii Y.
      • Xu G.
      • Dang T.C.
      • Hamashima T.
      • Matsushima T.
      • Yamamoto S.
      • Hattori Y.
      • Takatsuru Y.
      • Nabekura J.
      • Sasahara M.
      PDGFR-β as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia.
      Most importantly, these models allow us to understand the importance of endothelial-pericyte crosstalk in maintaining BBB integrity.
      In human AD, brain areas with reduced pericyte coverage of vessels show increased fibrin(ogen) and IgG extravasation demonstrating BBB leakage,
      • Sengillo J.D.
      • Winkler E.A.
      • Walker C.T.
      • Sullivan J.S.
      • Johnson M.
      • Zlokovic B.V.
      Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer's disease.
      and similar pathologic changes are seen in cSVD
      • Grinberg L.
      • Thal D.
      Vascular pathology in the aged human brain.
      (Figure 2). The findings of BBB impairment in patients with reduced pericyte vessel coverage are supported by reduced pericyte coverage in the naturally leaky ME
      • Pfau S.J.
      • Langen U.H.
      • Fisher T.M.
      • Prakash I.
      • Nagpurwala F.
      • Lozoya R.A.
      • Lee W.-C.A.
      • Wu Z.
      • Gu C.
      Vascular and perivascular cell profiling reveals the molecular and cellular bases of blood-brain barrier heterogeneity.
      and studies in rodents using pericyte-deficient mice seen by dextran tracer leakage around pericyte-deficient blood vessels, which worsens with increasing age,
      • Bell R.D.
      • Winkler E.A.
      • Sagare A.P.
      • Singh I.
      • LaRue B.
      • Deane R.
      • Zlokovic B.V.
      Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.
      a major risk factor for cSVD and AD dementias. In these mice, fibrin(ogen) and IgG leakage can occur with as little as 20% reduction in pericyte coverage.
      • Bell R.D.
      • Winkler E.A.
      • Sagare A.P.
      • Singh I.
      • LaRue B.
      • Deane R.
      • Zlokovic B.V.
      Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging.
      Pericyte degeneration is also associated with accumulation of fibrin(ogen) in the white matter of pericyte-deficient mice.
      • Montagne A.
      • Nikolakopoulou A.M.
      • Zhao Z.
      • Sagare A.P.
      • Si G.
      • Lazic D.
      • Barnes S.R.
      • Daianu M.
      • Ramanathan A.
      • Go A.
      • Lawson E.J.
      • Wang Y.
      • Mack W.J.
      • Thompson P.M.
      • Schneider J.A.
      • Varkey J.
      • Langen R.
      • Mullins E.
      • Jacobs R.E.
      • Zlokovic B.V.
      Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.
      Interestingly, fibrin(ogen) accumulation is much greater in the white matter regions of the brain compared with gray matter. Furthermore, fibrin(ogen) deposition in the white matter leads to loss of myelin, oligodendrocytes, and neuronal axons,
      • Montagne A.
      • Nikolakopoulou A.M.
      • Zhao Z.
      • Sagare A.P.
      • Si G.
      • Lazic D.
      • Barnes S.R.
      • Daianu M.
      • Ramanathan A.
      • Go A.
      • Lawson E.J.
      • Wang Y.
      • Mack W.J.
      • Thompson P.M.
      • Schneider J.A.
      • Varkey J.
      • Langen R.
      • Mullins E.
      • Jacobs R.E.
      • Zlokovic B.V.
      Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.
      similar to changes seen in patients with AD and cSVD,
      • Ihara M.
      • Polvikoski T.M.
      • Hall R.
      • Slade J.Y.
      • Perry R.H.
      • Oakley A.E.
      • Englund E.
      • O'Brien J.T.
      • Ince P.G.
      • Kalaria R.N.
      Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer's disease, and dementia with Lewy bodies.
      and cSVD rat models.
      • Sironi L.
      • Guerrini U.
      • Tremoli E.
      • Miller I.
      • Gelosa P.
      • Lascialfari A.
      • Zucca I.
      • Eberini I.
      • Gemeiner M.
      • Paoletti R.
      • Gianazza E.
      Analysis of pathological events at the onset of brain damage in stroke-prone rats: a proteomics and magnetic resonance imaging approach.
      The loss of oligodendrocytes may be, in part, attributable to the reduced vascular density and corresponding reduction in blood flow, leading to increased levels of hypoxia in white matter regions compared with that in the gray matter.
      • Montagne A.
      • Nikolakopoulou A.M.
      • Zhao Z.
      • Sagare A.P.
      • Si G.
      • Lazic D.
      • Barnes S.R.
      • Daianu M.
      • Ramanathan A.
      • Go A.
      • Lawson E.J.
      • Wang Y.
      • Mack W.J.
      • Thompson P.M.
      • Schneider J.A.
      • Varkey J.
      • Langen R.
      • Mullins E.
      • Jacobs R.E.
      • Zlokovic B.V.
      Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.
      This study highlights that regional differences in pericyte coverage within the CNS likely contribute to the differences in tissue susceptibility in dementia.
      In addition to overexpression of the Aβ precursor protein in transgenic mice, pericyte deficiency leads to reduced brain Aβ clearance mediated by low-density lipoprotein receptor–related protein 1 (LRP1). The reduction of LRP1-mediated clearance is not through changes in pericyte LRP1 expression but through reduction in pericyte numbers,
      • Sagare A.P.
      • Bell R.D.
      • Zhao Z.
      • Ma Q.
      • Winkler E.A.
      • Ramanathan A.
      • Zlokovic B.V.
      Pericyte loss influences Alzheimer-like neurodegeneration in mice.
      thus demonstrating an important role for pericytes in AD pathology, and in particular, limiting the formation of Aβ plaques. Endothelial cell LRP1 is important in maintaining BBB integrity; loss of endothelial LRP1 leads to BBB leakage, neuronal loss, and altered cognition in mice. This phenotype is attributable to cyclophilin A (CypA) matrix metalloproteinase (MMP)-9 pathway activation (discussed subsequently) and can be rescued by CypA inhibition or LRP1 reexpression.
      • Nikolakopoulou A.M.
      • Wang Y.
      • Ma Q.
      • Sagare A.P.
      • Montagne A.
      • Huuskonen M.T.
      • Rege S.V.
      • Kisler K.
      • Dai Z.
      • Körbelin J.
      • Herz J.
      • Zhao Z.
      • Zlokovic B.V.
      Endothelial LRP1 protects against neurodegeneration by blocking cyclophilin A.
      Loss of pericytes as well as changes to pericyte and endothelial protein expression likely affect not only BBB leakage and toxin clearance but also cerebral blood flow.

      Pericyte-Endothelial Crosstalk Controls Cerebral Blood Flow

      The integrity of the brain vasculature is important in maintaining perfusion to and oxygenation of the brain, which are vital because of a high metabolic demand and low energy storage capacity of the brain.
      • Muoio V.
      • Persson P.B.
      • Sendeski M.M.
      The neurovascular unit - concept review.
      There is disparity in the literature as to whether pericytes are able to directly control vessel diameter and hence blood flow.
      • Hall C.N.
      • Reynell C.
      • Gesslein B.
      • Hamilton N.B.
      • Mishra A.
      • Sutherland B.A.
      • O'Farrell F.M.
      • Buchan A.M.
      • Lauritzen M.
      • Attwell D.
      Capillary pericytes regulate cerebral blood flow in health and disease.
      • Hill R.A.
      • Tong L.
      • Yuan P.
      • Murikinati S.
      • Gupta S.
      • Grutzendler J.
      Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes.
      • Kisler K.
      • Nelson A.R.
      • Rege S.V.
      • Ramanathan A.
      • Wang Y.
      • Ahuja A.
      • Lazic D.
      • Tsai P.S.
      • Zhao Z.
      • Zhou Y.
      • Boas D.A.
      • Sakadžić S.
      • Zlokovic B.V.
      Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain.
      It is thought that pericytes lack contractile α-SMA and therefore have the ability to contract in response to stimuli. However, the presence of α-SMA in pericytes could be underreported because of filamentous-actin fixation or low cellular expression.
      • Grant R.
      • Hartmann D.
      • Underly R.
      • Berthiaume A.
      • Bhat N.
      • Shih A.
      Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.
      ,
      • Alarcon-Martinez L.
      • Yilmaz-Ozcan S.
      • Yemisci M.
      • Schallek J.
      • Kılıç K.
      • Can A.
      • Di Polo A.
      • Dalkara T.
      Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection.
      ,
      • Kim S.J.
      • Kim S.A.
      • Choi Y.A.
      • Park D.Y.
      • Lee J.
      Alpha-smooth muscle actin-positive perivascular cells in diabetic retina and choroid.
      Studies have found that retinal and brain pericytes possess α-SMA,
      • Alarcon-Martinez L.
      • Yilmaz-Ozcan S.
      • Yemisci M.
      • Schallek J.
      • Kılıç K.
      • Can A.
      • Di Polo A.
      • Dalkara T.
      Capillary pericytes express α-smooth muscle actin, which requires prevention of filamentous-actin depolymerization for detection.
      and the ensheathing pericyte subtype is α-SMA-positive.
      • Grant R.
      • Hartmann D.
      • Underly R.
      • Berthiaume A.
      • Bhat N.
      • Shih A.
      Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.
      Ensheathing pericytes respond to sensory stimuli, and vasodilate before arterioles via nitric oxide and prostaglandin E2.
      • Hall C.N.
      • Reynell C.
      • Gesslein B.
      • Hamilton N.B.
      • Mishra A.
      • Sutherland B.A.
      • O'Farrell F.M.
      • Buchan A.M.
      • Lauritzen M.
      • Attwell D.
      Capillary pericytes regulate cerebral blood flow in health and disease.
      Similar results are seen in another mouse model mediated by endothelial-secreted epoxyeicosatrienoates,
      • Zhang W.
      • Davis C.M.
      • Zeppenfeld D.M.
      • Golgotiu K.
      • Wang M.X.
      • Haveliwala M.
      • Hong D.
      • Li Y.
      • Wang R.K.
      • Iliff J.J.
      • Alkayed N.J.
      Role of endothelium-pericyte signaling in capillary blood flow response to neuronal activity.
      demonstrating endothelial-pericyte crosstalk in cerebral blood flow control. Disparities in the literature may be attributable to inconsistencies in terminology with first- to fourth-order branches from perforating arterioles termed capillaries instead of precapillary arterioles and their associated ensheathing pericytes being termed α-SMA–positive VSMCs. When different subtypes of pericytes are taken into account, studies appear to agree that precapillary ensheathing pericytes are able to regulate blood flow in vivo.
      • Grant R.
      • Hartmann D.
      • Underly R.
      • Berthiaume A.
      • Bhat N.
      • Shih A.
      Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.
      However, whether the capillary pericytes (mesh and thin-strand pericytes) are able to modulate cerebral blood flow is debatable.
      • Grant R.
      • Hartmann D.
      • Underly R.
      • Berthiaume A.
      • Bhat N.
      • Shih A.
      Organizational hierarchy and structural diversity of microvascular pericytes in adult mouse cortex.
      ,
      • Hill R.A.
      • Tong L.
      • Yuan P.
      • Murikinati S.
      • Gupta S.
      • Grutzendler J.
      Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes.
      ,
      • Hartmann D.A.
      • Berthiaume A.A.
      • Grant R.I.
      • Harrill S.A.
      • Koski T.
      • Tieu T.
      • McDowell K.P.
      • Faino A.V.
      • Kelly A.L.
      • Shih A.Y.
      Brain capillary pericytes exert a substantial but slow influence on blood flow.
      Cerebral capillary pericytes express the smooth muscle protein, myosin heavy chain, indicating some contractile ability.
      • Gonzales A.L.
      • Klug N.R.
      • Moshkforoush A.
      • Lee J.C.
      • Lee F.K.
      • Shui B.
      • Tsoukias N.M.
      • Kotlikoff M.I.
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      Contractile pericytes determine the direction of blood flow at capillary junctions.
      Furthermore, recent studies have found that capillary pericytes modulate blood vessel diameter more slowly after direct in vivo stimulation compared with surrounding ensheathing pericytes.
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      Brain capillary pericytes exert a substantial but slow influence on blood flow.
      Similar results were seen in retinal capillaries after direct stimulation, but this was not replicated in the cortical capillaries.
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      Contractile pericytes determine the direction of blood flow at capillary junctions.
      One hypothesis to explain this is that capillary pericytes require a stronger or different stimulus to respond.
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      Contractile pericytes determine the direction of blood flow at capillary junctions.
      Furthermore, imaging techniques may contribute to the ability to detect capillary diameter changes, and regional differences may occur; cerebral in vivo studies are currently limited to the cortex. Despite the debate over the ability of capillary pericytes to modulate cerebral blood flow, there are strong data supporting the role of ensheathing pericytes, particularly at vessel junctions,
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      Contractile pericytes determine the direction of blood flow at capillary junctions.
      in controlling blood flow response to NVU stimuli.
      Reduction in cerebral blood flow occurs in the gray matter of patients with cognitive impairment,
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