title: Dense-core senile plaques in the Flemish variant of Alzheimer's disease are vasocentric.
abstract: Alzheimer's disease (AD) is characterized by deposition of beta-amyloid (Abeta) in diffuse and senile plaques, and variably in vessels. Mutations in the Abeta-encoding region of the amyloid precursor protein (APP) gene are frequently associated with very severe forms of vascular Abeta 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 Abeta analyses, we demonstrated that in contrast to other familial AD cases with predominant brain Abeta42, Flemish AD patients predominantly deposit Abeta40. 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 Abeta facilitate progressive Abeta deposition in vascular walls that in addition to causing strokes, initiates formation of dense-core senile plaques in the Flemish variant of AD.
authors.affiliation: Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. samir.kumarsingh@ua.ac.be
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
authors.forename: Patrick
authors.initials: P
authors.lastname: Cras
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: John M
authors.initials: JM
authors.lastname: Kros
authors.forename: Johan
authors.initials: J
authors.lastname: van Swieten
authors.forename: Ursula
authors.initials: U
authors.lastname: Lübke
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick
authors.forename: Sally
authors.initials: S
authors.lastname: Serneels
authors.forename: Krist'l
authors.initials: K
authors.lastname: Vennekens
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: Eric
authors.initials: E
authors.lastname: Van Marck
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Martin
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D002560:Cerebrovascular Circulation; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D058225:Plaque, Amyloid / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor