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(American Journal of Pathology. 2002;161:507-520.)
© 2002 American Society for Investigative Pathology

Regular Articles

Dense-Core Senile Plaques in the Flemish Variant of Alzheimer’s Disease Are Vasocentric

Samir Kumar-Singh^*, Patrick Cras, Rong Wang, John M. Kros, Johan van Swieten^¶, Ursula Lübke, Chantal Ceuterick, Sally Serneels^*, Krist’l Vennekens^*, Jean-Pierre Timmermans^||, Eric Van Marck^**, Jean-Jacques Martin, Cornelia M. van Duijn^* and Christine Van Broeckhoven^*

From the Department of Molecular Genetics,^*Flanders Interuniversity Institute for Biotechnology, and the Laboratories of Neurology and Neuropathology, Born-Bunge Foundation, and the Laboratories of Histology^||and Pathology,^**University of Antwerp, Antwerp, Belgium; the Department of Human Genetics,Mount Sinai School of Medicine, New York, New York; the Departments of Pathologyand Neurology,^¶University Hospital Rotterdam, Rotterdam, The Netherlands; and the Department of Epidemiology and Biostatistics,Erasmus University, Rotterdam, The Netherlands

Alzheimer’s disease (AD) is characterized by deposition of ß-amyloid (Aß) in diffuse and senile plaques, and variably in vessels. Mutations in the Aß-encoding region of the amyloid precursor protein (APP) gene are frequently associated with very severe forms of vascular Aß deposition, sometimes also accompanied by AD pathology. We earlier described a Flemish APP (A692G) mutation causing a form of early-onset AD with a prominent cerebral amyloid angiopathy and unusually large senile plaque cores. The pathogenic basis of Flemish AD is unknown. By image and mass spectrometric Aß analyses, we demonstrated that in contrast to other familial AD cases with predominant brain Aß42, Flemish AD patients predominantly deposit Aß40. On serial histological section analysis we further showed that the neuritic senile plaques in APP692 brains were centered on vessels. Of a total of 2400 senile plaque cores studied from various brain regions from three patients, 68% enclosed a vessel, whereas the remainder were associated with vascular walls. These observations were confirmed by electron microscopy coupled with examination of serial semi-thin plastic sections, as well as three-dimensional observations by confocal microscopy. Diffuse plaques did not associate with vessels, or with neuritic or inflammatory pathology. Together with earlier in vitro data on APP692, our analyses suggest that the altered biological properties of the Flemish APP and Aß facilitate progressive Aß deposition in vascular walls that in addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish variant of AD.

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