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From the Nathan S. Kline Institute for Psychiatric
Research,*
Orangeburg, New York; the New York University
School of Medicine,
New York, New York; the
Department of Pathology (Neuropathology) and
Neurology,
The Johns Hopkins University
School of Medicine, Baltimore, Maryland; and the Department of
Neurology,§
Massachusetts General Hospital,
Boston, Massachusetts
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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4 allele of
APOE, however, accentuated early endosome enlargement
at preclinical stages of AD. By contrast, endosomes were normal
in size at advanced stages of familial AD caused by mutations of
presenilin 1 or 2, indicating that altered endocytosis is not a
consequence of Aß deposition. These results identify EP activation as
the earliest known intraneuronal change to occur in sporadic
AD, the most common form of AD. Given the important role of the
EP in Aß peptide generation and ApoE function, early
endosomal abnormalities provide a mechanistic link between EP
alterations, genetic susceptibility factors, and Aß
generation and suggest differences that may be involved in Aß
generation and ß amyloidogenesis in subtypes of AD.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Early endosomes are the first major sorting station on the endocytic pathway and the site of internalization and initial processing of proteins relevant to AD pathogenesis like the ß protein precursor (ßPP) and apolipoprotein E (ApoE). Early endosomes are also a major site of amyloid ß (Aß) peptide production in normal cells and mediate the cellular uptake of Aß and soluble iPP. Numerous studies have implicated both the secretory pathway, specifically the endoplasmic reticulum1-4 and Golgi apparatus5-8 and EP9-12 in ßPP processing and the production of Aß 1–40, Aß 1–42, or both.
In previous studies of sporadic Alzheimer’s disease (SAD)
brain, we found that the volumes of neuronal early endosomes were, on
average, threefold larger than normal, which is a morphological change
known to be associated with increased EP activity.13,14
In
addition, levels of immunoreactive cathepsins D and B in both their
pro- and mature forms were elevated within enlarged
endosomes,15
coinciding in these neurons with increases of
cation-dependent mannose 6-phosphate receptors, which mediates the
delivery of acid hydrolases, including cathepsins, to early endosomes.
One of the cathepsins mistrafficked in these models, cathepsin D, has
been shown to have ßPP ß/
secretase activity toward model
peptides, recombinant ßPP and the C-100 fragment of
ßPP.16-19
Our previous studies have demonstrated that
lysosomal system (LS) activation evidenced by an increase in gene
expression and accumulation of lysosomes is an early and distinctive
response of neurons in SAD and Down syndrome (DS).20-22
Neurons exhibiting overt atrophy or neurofibrillary change display
robust accumulation of hydrolase-positive lysosomes and lipofuscin
granules which are then released into the parenchyma after cell lysis.
These compartments containing a battery of enzymatically competent
hydrolases, persist in the extracellular space in association with
deposits of Aß in both senile and diffuse plaques.21-23
By immunocytochemistry, we have found that in cases of familial
Alzheimer’s disease (FAD) linked to presenilin (PS) 1 and PS2
mutations, LS activation was greater in pyramidal neurons in cortical
laminae III and V than in SAD.24
Neuronal populations that
are less vulnerable in SAD, such as those in cortical lamina II and IV
of the prefrontal cortex, showed marked LS up-regulation in
PS-FAD. Like SAD, senile plaques in PS-FAD brains displayed
intense hydrolase immunoreactivity.24
Compared with SAD,
PS-FAD promotes an earlier and excessive deposition of Aß
1–42.25,26
The enhanced LS response seen in PS-FAD is
consistent with in vitro studies showing that Aß 1–42
accumulates in late endosomes and lysosomes.27
In the present study, we further characterized the EP in SAD using
antibody probes to molecules known to regulate specific aspects of the
endocytic process. Moreover, we investigated the onset of EP
dysfunction in the brains of nondemented individuals exhibiting the
earliest Alzheimer-like pathological changes restricted to the
entorhinal cortex and hippocampus. The analysis was extended to earlier
stages of pathogenesis in brains from fetuses and juveniles with DS
(trisomy 21), a form of mental retardation invariably associated with
the development of AD neuropathology after age 40.28
Finally, we analyzed the influence of normal aging, APOE genotype, and
PS mutations on endosome morphology in relation to the evolution of AD
neuropathology. Our results show that early endosomal abnormalities are
the earliest neuropathological alteration yet to be identified in SAD.
Their appearance is greatly accelerated by triplication of the distal
half of the long arm of chromosome 21 (DS). Inheritance of the APOE
4 allele, which substantially increases the risk for developing AD
and promotes earlier disease onset29
also promoted earlier
appearance of endosome enlargement. Finally, in a variety of
neurodegenerative diseases and, significantly, in severely affected
individuals with FAD linked to four different mutations of PS1 and the
Asn141-Ile mutation of PS2, endosomes were normal in size. These
observations indicate that the neuronal endosomal response seen in AD
is highly disease-specific and does not seem to be a secondary effect
of Aß deposition. An understanding of the origins and effects of this
abnormal endocytic response should provide important insight into
pathogenic mechanisms in sporadic AD, the most common and least well
understood form of AD.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Postmortem brain tissue from 15 elderly, nondemented individuals
were examined according to The Consortium to Establish a Registry for
Alzheimer’s Disease30
and the criteria proposed by Mirra
et al31
and staged according to Braak and
Braak32
and diagnosed with neuropathological evidence of
early-stage Alzheimer’s disease (AD) (neocortex devoid of plaques,
Braak stage 0; transentorhinal, entorhinal cortex/hippocampus, sparse
plaques, Braak stage I–III). Another 10 age-matched 62- to 80-year-old
cases (control group A) were evaluated similarly and found to be
neuropathologically normal controls (isocortex, entorhinal
cortex/hippocampus devoid of plaques and neurofibrillary tangles).
Fixed tissue was obtained from the Bronx Veteran’s Administration
Medical Center and Mt. Sinai Medical Centers, the Harvard Brain Tissue
Resource Center at McLean Hospital (Belmont, MA), and the
Neuropathology Core Facility of the Massachusetts Alzheimer’s Disease
Resource Center (Massachusetts General Hospital, Boston, MA). Clinical
records indicated that all subjects were cognitively normal and 60% of
these cases were neuropsychologically evaluated and assigned the
clinical dementia rating score of 0 (cognitively intact). All brains
were characterized neuropathologically by hematoxylin and eosin,
Bielschowsky silver stain, thioflavin S, Aß, and 
immunoreactivities. Early-stage AD cases were found to have AD
neuropathological changes limited to the entorhinal cortex/hippocampus.
Because AD neuropathology begins in the entorhinal cortex/hippocampus
and later spreads to neocortical areas, we evaluated the EP in
formalin-fixed tissue blocks of the entorhinal cortex/hippocampus
containing neuropathological changes suggestive of AD and prefrontal
cortex at stages with no neuropathological evidence of
AD.30-32
APOE genotyping was performed in the laboratory
of Dr. Bradley Hyman at the Massachusetts General Hospital, Boston, MA,
using a modified polymerase chain reaction technique.33
Tissue from seven cases of early-stage DS ranging in age from 28 weeks
of gestation to 12 years and an equal number of young age-matched
control cases were procured from the Johns Hopkins University Brain
Resource Center, Baltimore, MD. Postmortem tissue from 15 confirmed
cases of early-onset FAD linked to various mutations of the PS gene (12
PS1-FAD cases; three PS2-FAD cases) were obtained from a number of
individual investigators and tissue resource centers including the
Joseph and Kathleen Bryan Alzheimer Disease Research Center, the Duke
University Medical School, the Medical College of Pennsylvania and
Hahnemann University, and the National Neurological Research Specimen
Bank/Veteran’s Administration Medical Center. Although the cognitive
status of the PS-FAD cases was unknown, all brains used in this study
exhibited evidence of advanced stage AD neuropathology (>30 neuritic
plaques per high power field, Braak stage IV–V) in the
entorhinal cortex, hippocampus, and frontal cortex). A second group of
22 normal controls (control group B) ranging in age from 1 year to 85
years of age were collected from the Harvard Brain Tissue Resource
Center and the Massachusetts Alzheimer’s Disease Resource Center
and used solely for the normal aging study. Additional postmortem
tissues from individuals with the neuropathological diagnosis of
encephalopathy, Pick’s disease, Lewy body disease, Huntington’s
disease–grade three, amyotrophic lateral sclerosis (ALS) and
progressive supranuclear palsy were procured from the Harvard Brain
Tissue Resource Center and Massachusetts Alzheimer’s Disease Resource
Center.
Antibodies
Immunocytochemical studies were performed as previously
described34
using polyclonal antibodies raised against a
synthetic peptide corresponding to amino acids 193–211 of the
C-terminal domain of the human GTP-binding protein, rab5, and amino
acids 191–210 of rab4 of human origin (Santa Cruz Biotechnology, Inc.,
Santa Cruz, CA); an affinity-purified polyclonal antibody raised
against a synthetic peptide corresponding to an amino acid sequence
mapping to the C-terminus of human rabaptin 5 (Santa Cruz Biotechnology
Inc.); a monoclonal antibody generated against the N-terminus (amino
acids 3–281) of human early endosomal antigen 1 (Transduction
Laboratories, Lexington, KY); and a monoclonal antibody generated
against a synthetic peptide of human Aß 17–24 (4G8) (Senetek, Drug
Delivery Technologies, Inc., St. Louis, MO). A monoclonal antibody,
MC-1, which reacts with two conformationally constrained domains of
in paired helical filaments (PHF) was a generous gift of Dr.
Peter Davies (Department of Pathology, Albert Einstein College of
Medicine, Bronx, NY). Details on the generation and
immunospecificity of MC-1 have been reported previously.35
Brain tissue used for immunocytochemical analyses was immersion-fixed
in cold 10% phosphate-buffered formalin (0.15 mol/L), pH 7.4.
Immunocytochemistry
Immunoreactivity was demonstrated on 30- to 40-µm-thick vibratome sections as previously described.34 Negative controls included tissue sections incubated in the absence of primary antisera.
Morphometric Analysis
Vibratome sections of the prefrontal cortex of all early-stage AD, FAD, non-AD neurodegenerative disorders, and control cases were immunostained in tandem under identical conditions with rab5 antiserum. Background staining intensities among all sections were comparable and all neurons were intact. Small, medium, and large pyramidal neurons from lamina III of the prefrontal cortex (Brodmann area 10) were selected at random and the cross-sectional area, number, average, and total early endosomal volume per neuron were analyzed for each neuron as previously described.15,22
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To establish the initial appearance of endosomal alterations in relation to Aß deposition or neurofibrillary change, we examined cognitively and neuropathologically-normal elderly individuals and two affected populations. The first affected population referred to as "pre-AD" was composed of cognitively-normal elderly individuals who after death were diagnosed with neuropathological evidence early stage/possible AD based on the presence of Alzheimer-like pathology in the transentorhinal and entorhinal cortex and hippocampus (sparse plaques, Braak stage I–III). Cross-sectional neuropathological data analyses using several neuropathological guidelines30-32 have shown this neuropathological pattern to represent the earliest stages in the evolution toward AD. The second group included individuals with DS who are at very high risk to develop AD36 but were studied at very young ages when the brains showed no evidence of neuropathology.
In brain sections immunolabeled with anti-rab5, a specific marker for
early endosomes,37
neurons in brains from control subjects
displayed endosomes of normal size.13,14,38
By contrast,
in the pre-AD cases, abnormally large endosomes ranging from 400 to 620
nm were prominent in the majority of pyramidal neurons in laminae II of
the entorhinal cortex and CA2 and CA3 fields of the hippocampus and in
laminae III and V of the prefrontal cortex. Immunolabeling studies on
serial adjacent tissue sections of the prefrontal cortex using 4G8
against Aß 17–24 or MC-1, against a conformation of believed to
mark the earliest stages of neurofibrillary pathology, or
double-immunofluorescence studies with one of these antibodies and rab5
demonstrated that neuronal early endosomal enlargement could be
detected in the absence of extracellular Aß accumulation or
neurofibrillary pathology (Figure 1)
.
Morphometric analyses performed on 25 neocortical neurons from lamina
III of each of the 15 pre-AD cases and 11 controls showed
endosomal volume to be nearly twofold larger in the pre-AD cases than
normal (control mean, 1.88%, SEM ± 0.066 versus
pre-AD mean, 3.68%, SEM ± 0.093; Figure 1
) and less than the
increase in endosomal volume we observed previously in confirmed
moderate-severe SAD cases.15
The numbers of rab5-positive
endosomes in the pre-AD cases were similar to those in control brains
(control average = 55, SEM ± 1.87 endosomes/cell; possible
AD = 50, SEM ± 1.80 endosomes/cell). Cortical pyramids in
lamina V displayed similar alterations (data not shown).
|
.
Rab4, another GTPase like rab5, plays a complementary role to rab5 by
directing the recycling of early endosomes to the cell
surface.42
Serial adjacent tissue sections of frontal
cortex from AD brains labeled with anti-rab4 antiserum showed a marked
qualitative increase compared to controls in the expression of rab4 in
pyramidal neurons which was principally localized within small vesicles
of sizes consistent with their being recycling vesicles. The
increased level of rab4 detected by immunocytochemistry associated with
the AD cases was confirmed by Western blot analysis. Differences in the
level of rab4 immunoreactive protein quantitated by scan analysis were
nearly twofold higher in the early-stage AD brains versus
controls (Figure 1j)
and equivalent to that found in moderate to severe
stage cases of AD (data not shown; control mean = 345.1; pre-AD
mean = 560.6, P > 0.05).
APOE 4 Genotype Promotes EP Activation in Early-Stage SAD
Because ApoE function in neurons is dependent on EP activity, we
investigated the influence of APOE genotype on endosome size. By
stratifying the quantitative data on the AD cases in Figure 1
according
to APOE genotype, we found that the mean total endosomal volume per
neuron in brains from the possible AD cases carrying one or two APOE
4 alleles was nearly 50% larger than the cases carrying APOE 2
or 3 (2, 3 group mean = 3.18%, SEM ± 0.095; 4
group mean = 4.68%, SEM ± 0.206; P <
0.005) (Figure 1)
. That the 4 allele influences clinical disease
onset, but not progression,43,44
parallels our observation
that endosomal abnormalities are accelerated by the 4 allele at
earliest stages of disease but not at moderate to severe stages of
clinical disease where we found no detectable differences in neuronal
endosomal volume in AD brains from individuals with one or both 4
alleles as compared to those carrying 3 or 2 alleles (mean
endosomal volume 3, 2 = 4.99, SEM ± 0.10; mean
endosomal volume 4 = 5.29, SEM ± 0.24, P
= 0.112).
EP Abnormalities Precede AD Neuropathology by Decades in DS
Individuals with DS invariably develop AD by age 50. To
investigate the earliest appearance of endosomal abnormalities, we
immunolabeled tissue sections of the prefrontal cortex from seven cases
of fetal, infant, and young DS patients ranging in age from 28 weeks of
gestation to 12 years with anti-rab5 antiserum. Many pyramidal neurons
contained early endosomes of abnormally large sizes that were not seen
in neurons from the age-matched young control cases examined (Figure 2)
. Qualitative differences in endosomal
size were evident in 21% (SEM ± 2%) of pyramidal neurons
(n = 50) per high-power field in the youngest
cases (ages 28 weeks to 5 years) and increased to 40% (SEM ±
5%) with age (between 5 and 12 years of age). Although the number of
neurons containing enlarged endosomes in the DS brains increased with
age, the magnitude of endosomal enlargement in affected neurons in
these DS cases was equivalent to that seen in pyramidal neurons from
six cases of adult DS ranging in age from 25 to 56 years.
|
We next determined the specificity of endosomal enlargement to SAD
and DS by examining severely affected neuronal populations from several
non-AD neurodegenerative diseases including cases of encephalitis,
Pick’s disease, Lewy body dementia, Huntington’s disease, progressive
supranuclear palsy, and amyotrophic lateral sclerosis. We found that
within the various affected neuronal populations of the non-AD
neurodegenerative group, early endosomal size was similar to that seen
in neurologically normal controls (average mean endosomal volume:
control = 1.88%; SEM ± 0.066; non-AD neurodegenerative
diseases = 2.26%, SEM ± 0.067, P = 0.137)
(Figure 3)
.
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. EP Activation Distinguishes Subtypes of AD
We find that, in all forms of AD, the neuronal expression of
lysosomal proteases (cathepsins) is strongly up-regulated and lysosomes
markedly accumulate.20-22
Because it might be anticipated
that certain cellular alterations arising at the earliest stages of AD
pathogenesis may develop in some forms of AD and not in others, we
assessed whether the same structural abnormalities of early endosomes
seen in SAD and accelerated in development in late-onset FAD-APOE 4
and DS, were also promoted by mutations of PS causing present
early-onset FAD. Serial adjacent tissue sections from the prefrontal
cortex of 12 patients with moderate to severe FAD caused by any of four
different mutations in PS, immunolabeled with rab5 and 4G8, displayed
no apparent early endosomal abnormalities in neurons despite abundant
Aß plaques (Figure 4)
. Morphometric
analysis showed that the average endosomal volume per neuron in the
PS-FAD cases was similar to that of normal controls (control mean
= 1.88%, SEM ± 0.066; PS-FAD mean = 2.22%, SEM ±
0.061; P = 0.097) (Figure 4)
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The activation of the EP is a disease-selective response of neurons in
populations susceptible to AD. Our inability to detect this response in
other neurodegenerative diseases establishes that it is not a
generalized response to neuronal injury or degeneration. We observed,
however, that its onset is substantially influenced by genetic effects
relevant to AD pathogenesis. The appearance of early endosome
abnormalities in some neurons before birth in DS implies that dosage of
particular genes on chromosome 21 greatly accelerates the development
of the EP activation. Triplication of the ßPP gene, by itself, may be
an insufficient stimulus because ßPP overexpression in mice does not
detectably alter endocytosis whereas, in the partial trisomy 16 mouse
(Ts65Dn), endosome enlargement is comparable to that in its human
counterpart, trisomy 21 (unpublished data; AM Cataldo et al,
manuscript in preparation). We also found that the APOE 4 allele
accentuates the EP response in early AD. At later stages of disease
when the EP response is fully developed, no APOE allele influence is
apparent suggesting that, like its effect on clinical disease, APOE
genotype accelerates the onset but not the final magnitude of the EP
response. These influences of APOE alleles support the pathogenic
relevance of EP abnormalities to AD pathogenesis and are consistent
with evidence that ApoE binding to its neuronal receptor activates
endocytosis47,48
and that ApoE interacts with ßPP in the
endosomal compartment.48
The neuronal EP activation observed in this study is the only known
feature of cellular AD neuropathology that differentiates subtypes of
AD. Because AD is heterogeneous in etiology, it could well be
anticipated that cellular responses that are close to the primary
initiating events of AD would not only appear early but also may not be
shared by all AD subtypes. The different alterations of calcium
homeostasis or Aß generating pathways associated with various FAD
mutations in fibroblasts and transgenic mouse models of FAD may be
biochemical evidence of these distinctive early
pathways.49-52
The absence of an EP response in PS-FAD is
paralleled by recent findings that, unlike SAD and DS, PS-FAD does not
seem to be influenced by APOE genotype.53,54
The latter
finding is consistent with the view that PS, which resides principally
in the endoplasmic reticulum55
promotes Aß
generation and disease progression mainly via nonendocytic
routes55
that might not be expected to be influenced by
ApoE. Together, these findings imply that activation of endocytosis and
its accentuation by APOE 4 genotype constitute a mechanism
particularly relevant to the most common, sporadic form of AD, in which
initial stages of pathogenesis are unknown.
A second explanation for the absence of an endosomal response in the PS-FAD cases comes from a recent study by Van Uden et al56 showing a link between mutant PS expression and down-regulation of the LDL receptor-related protein, which modulates the cellular uptake of AD-associated proteins such as ßPP and ApoE. Other factors that could explain the difference in endocytic response between AD subtypes would be the greater rate of neurodegeneration in PS-FAD versus SAD57 which could limit the window within which endosomal disturbances could be detected. Evidence against this notion is supported by our studies showing the absence of endosomal abnormalities in primary fibroblasts from PS-FAD subjects and in neurons from PS/ßPP transgenic mice (unpublished observations).
Altered endocytosis is likely to have a major influence on pathogenic events in AD. Although EP activation in AD may begin as a compensatory response, chronic activation produces functional, morphological, and compositional effects on the EP that could increase neuronal vulnerability. Endocytic activation may, by itself, lead to sequestration and inappropriate degradation of vital plasma membrane proteins, growth factors, or receptors in the early endosome. Such an effect on neuronal glucose transporters may be one mechanism for compromised glucose uptake in AD58,59 and has direct implications for reduced cell viability. The EP is also the portal of entry for oxidizable substrates, such as Aß and apolipoproteins which could selectively damage lysosome integrity or impair its functions. Endocytic activation is likely to contribute to the robust up-regulation of the LS as seen in AD brain, which has been linked to increased neuronal vulnerability.60-62 LS activation progressively worsens with advancing disease and accounts, at least in part, for cell dysfunction leading to cell loss.63-66 The pathogenic significance endosomal abnormalities in AD is further indicated by the recent identification of a ß-secretase (BACE) which was found to be enriched in endosomes and to have an optimal pH requirement consistent with activity in early endosomes.67 Therefore, it is noteworthy that, in AD, we find hydrolase trafficking to early endosomes to be enhanced.15 Recent evidence using transfected cell lines that mimic the enhanced trafficking of hydrolases to early endosomes seen in human brain, secrete two- to threefold higher levels of Aß40 and Aß 42, respectively.68 Aß production, Aß clearance, or both could be affected by EP abnormalities and, based on current knowledge of endosome biology, be subject to influences by ApoE. In light of the importance of ApoE in Aß deposition, early endosomes, the only known site where ApoE, ßPP, and Aß are known to co-exist, represents an attractive site in SAD and DS brain to initiate Aß formation—a process favored by acidic conditions.18,69-73 This notion is further strengthened by our recent findings showing that in cases of early-stage AD and DS, the appearance of endosomal abnormalities coincides with increased soluble Aß levels and the presence of intraneuronal Aß immunoreactivity which co-localizes predominantly to enlarged endosomes (Cataldo et al, 2000, in preparation). However, we cannot exclude the possibility that elevated Aß levels could contribute to or cause endosomal alterations that represent an attempt by cells to clear Aß. Further studies of new cell and animal models to investigate these cellular pathways, the roles of which are poorly understood in AD, are expected to help clarify the cellular pathogenesis of AD and to identify targets for therapeutic intervention.
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Acknowledgements |
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Footnotes |
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Supported in part by National Institutes of Health grants AG 10916 (to R. A. N.) and AG14762 (to A. M. C.).
Accepted for publication March 14, 2000.
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Z.-S. Ji, K. Mullendorff, I. H. Cheng, R. D. Miranda, Y. Huang, and R. W. Mahley Reactivity of Apolipoprotein E4 and Amyloid beta Peptide: LYSOSOMAL STABILITY AND NEURODEGENERATION J. Biol. Chem., February 3, 2006; 281(5): 2683 - 2692. [Abstract] [Full Text] [PDF]
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K. Offe, S. E. Dodson, J. T. Shoemaker, J. J. Fritz, M. Gearing, A. I. Levey, and J. J. Lah The Lipoprotein Receptor LR11 Regulates Amyloid beta Production and Amyloid Precursor Protein Traffic in Endosomal Compartments J. Neurosci., February 1, 2006; 26(5): 1596 - 1603. [Abstract] [Full Text] [PDF]
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T. Van Dooren, D. Muyllaert, P. Borghgraef, A. Cresens, H. Devijver, I. Van der Auwera, S. Wera, I. Dewachter, and F. Van Leuven Neuronal or Glial Expression of Human Apolipoprotein E4 Affects Parenchymal and Vascular Amyloid Pathology Differentially in Different Brain Regions of Double- and Triple-Transgenic Mice Am. J. Pathol., January 1, 2006; 168(1): 245 - 260. [Abstract] [Full Text] [PDF]
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 S. Chang, T. r. Ma, R. D. Miranda, M. E. Balestra, R. W. Mahley, and Y. Huang Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity PNAS, December 20, 2005; 102(51): 18694 - 18699. [Abstract] [Full Text] [PDF]
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S. E. Perez, O. Lazarov, J. B. Koprich, E.-Y. Chen, V. Rodriguez-Menendez, J. W. Lipton, S. S. Sisodia, and E. J. Mufson Nigrostriatal Dysfunction in Familial Alzheimer's Disease-Linked APPswe/PS1{Delta}E9 Transgenic Mice J. Neurosci., November 2, 2005; 25(44): 10220 - 10229. [Abstract] [Full Text] [PDF]
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M. Arbel, I. Yacoby, and B. Solomon Inhibition of amyloid precursor protein processing by {beta}-secretase through site-directed antibodies PNAS, May 24, 2005; 102(21): 7718 - 7723. [Abstract] [Full Text] [PDF]
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D. Langui, N. Girardot, K. H. El Hachimi, B. Allinquant, V. Blanchard, L. Pradier, and C. Duyckaerts Subcellular Topography of Neuronal A{beta} Peptide in APPxPS1 Transgenic Mice Am. J. Pathol., November 1, 2004; 165(5): 1465 - 1477. [Abstract] [Full Text] [PDF]
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F. M. Harris, W. J. Brecht, Q. Xu, R. W. Mahley, and Y. Huang Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase: MODULATION BY ZINC J. Biol. Chem., October 22, 2004; 279(43): 44795 - 44801. [Abstract] [Full Text] [PDF]
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 P. Coleman, H. Federoff, and R. Kurlan A focus on the synapse for neuroprotection in Alzheimer disease and other dementias Neurology, October 12, 2004; 63(7): 1155 - 1162. [Abstract] [Full Text] [PDF]
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 N. Gupta-Rossi, E. Six, O. LeBail, F. Logeat, P. Chastagner, A. Olry, A. Israel, and C. Brou Monoubiquitination and endocytosis direct {gamma}-secretase cleavage of activated Notch receptor J. Cell Biol., July 5, 2004; 166(1): 73 - 83. [Abstract] [Full Text] [PDF]
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R. H. Takahashi, C. G. Almeida, P. F. Kearney, F. Yu, M. T. Lin, T. A. Milner, and G. K. Gouras Oligomerization of Alzheimer's {beta}-Amyloid within Processes and Synapses of Cultured Neurons and Brain J. Neurosci., April 7, 2004; 24(14): 3592 - 3599. [Abstract] [Full Text] [PDF]
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J. Raber Androgens, ApoE, and Alzheimer's Disease Sci. Aging Knowl. Environ., March 17, 2004; 2004(11): re2 - re2. [Abstract] [Full Text] [PDF]
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W. J. Brecht, F. M. Harris, S. Chang, I. Tesseur, G.-Q. Yu, Q. Xu, J. Dee Fish, T. Wyss-Coray, M. Buttini, L. Mucke, et al. Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice J. Neurosci., March 10, 2004; 24(10): 2527 - 2534. [Abstract] [Full Text] [PDF]
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R. A. Nixon Niemann-Pick Type C Disease and Alzheimer's Disease: The APP-Endosome Connection Fattens Up Am. J. Pathol., March 1, 2004; 164(3): 757 - 761. [Abstract] [Full Text] [PDF]
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L.-W. Jin, I. Maezawa, I. Vincent, and T. Bird Intracellular Accumulation of Amyloidogenic Fragments of Amyloid-{beta} Precursor Protein in Neurons with Niemann-Pick Type C Defects Is Associated with Endosomal Abnormalities Am. J. Pathol., March 1, 2004; 164(3): 975 - 985. [Abstract] [Full Text] [PDF]
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M.-S. Lee, S.-C. Kao, C. A. Lemere, W. Xia, H.-C. Tseng, Y. Zhou, R. Neve, M. K. Ahlijanian, and L.-H. Tsai APP processing is regulated by cytoplasmic phosphorylation J. Cell Biol., October 13, 2003; 163(1): 83 - 95. [Abstract] [Full Text] [PDF]
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O. M. Grbovic, P. M. Mathews, Y. Jiang, S. D. Schmidt, R. Dinakar, N. B. Summers-Terio, B. P. Ceresa, R. A. Nixon, and A. M. Cataldo Rab5-stimulated Up-regulation of the Endocytic Pathway Increases Intracellular {beta}-Cleaved Amyloid Precursor Protein Carboxyl-terminal Fragment Levels and A{beta} Production J. Biol. Chem., August 15, 2003; 278(33): 31261 - 31268. [Abstract] [Full Text] [PDF]
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A. M. Cataldo, S. Petanceska, C. M. Peterhoff, N. B. Terio, C. J. Epstein, A. Villar, E. J. Carlson, M. Staufenbiel, and R. A. Nixon App Gene Dosage Modulates Endosomal Abnormalities of Alzheimer's Disease in a Segmental Trisomy 16 Mouse Model of Down Syndrome J. Neurosci., July 30, 2003; 23(17): 6788 - 6792. [Abstract] [Full Text] [PDF]
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B. W. McColl, D. I. Graham, C. J. Weir, F. White, and K. Horsburgh Endocytic Pathway Alterations in Human Hippocampus after Global Ischemia and the Influence of APOE Genotype Am. J. Pathol., January 1, 2003; 162(1): 273 - 281. [Abstract] [Full Text] [PDF]
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R. H. Takahashi, T. A. Milner, F. Li, E. E. Nam, M. A. Edgar, H. Yamaguchi, M. F. Beal, H. Xu, P. Greengard, and G. K. Gouras Intraneuronal Alzheimer A{beta}42 Accumulates in Multivesicular Bodies and Is Associated with Synaptic Pathology Am. J. Pathol., November 1, 2002; 161(5): 1869 - 1879. [Abstract] [Full Text] [PDF]
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P. M. Mathews, Y. Jiang, S. D. Schmidt, O. M. Grbovic, M. Mercken, and R. A. Nixon Calpain Activity Regulates the Cell Surface Distribution of Amyloid Precursor Protein. INHIBITION OF CALPAINS ENHANCES ENDOSOMAL GENERATION OF beta -CLEAVED C-TERMINAL APP FRAGMENTS J. Biol. Chem., September 20, 2002; 277(39): 36415 - 36424. [Abstract] [Full Text] [PDF]
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J. L. Rosenfeld, R. H. Moore, K.-P. Zimmer, E. Alpizar-Foster, W. Dai, M. N. Zarka, and B. J. Knoll Lysosome proteins are redistributed during expression of a GTP-hydrolysis-defective rab5a J. Cell Sci., March 14, 2002; 114(24): 4499 - 4508. [Abstract] [Full Text] [PDF]
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P. M. Mathews, C. B. Guerra, Y. Jiang, O. M. Grbovic, B. H. Kao, S. D. Schmidt, R. Dinakar, M. Mercken, A. Hille-Rehfeld, J. Rohrer, et al. Alzheimer's Disease-related Overexpression of the Cation-dependent Mannose 6-Phosphate Receptor Increases Abeta Secretion. ROLE FOR ALTERED LYSOSOMAL HYDROLASE DISTRIBUTION IN beta -AMYLOIDOGENESIS J. Biol. Chem., February 8, 2002; 277(7): 5299 - 5307. [Abstract] [Full Text] [PDF]
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A. Deng, M. C. Irizarry, R. M. Nitsch, J. H. Growdon, and G. W. Rebeck Elevation of Cystatin C in Susceptible Neurons in Alzheimer's Disease Am. J. Pathol., September 1, 2001; 159(3): 1061 - 1068. [Abstract] [Full Text] [PDF]
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J. Y. Sung, J. Kim, S. R. Paik, J. H. Park, Y. S. Ahn, and K. C. Chung Induction of Neuronal Cell Death by Rab5A-dependent Endocytosis of alpha -Synuclein J. Biol. Chem., July 13, 2001; 276(29): 27441 - 27448. [Abstract] [Full Text] [PDF]
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