title: Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.
abstract: The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.
authors.affiliation: Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Antwerpen, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Dermaut
authors.forename: S
authors.initials: S
authors.lastname: Kumar-Singh
authors.forename: C
authors.initials: C
authors.lastname: De Jonghe
authors.forename: M
authors.initials: M
authors.lastname: Cruts
authors.forename: A
authors.initials: A
authors.lastname: Löfgren
authors.forename: U
authors.initials: U
authors.lastname: Lübke
authors.forename: P
authors.initials: P
authors.lastname: Cras
authors.forename: R
authors.initials: R
authors.lastname: Dom
authors.forename: P P
authors.initials: PP
authors.lastname: De Deyn
authors.forename: J J
authors.initials: JJ
authors.lastname: Martin
authors.forename: C
authors.initials: C
authors.lastname: Van Broeckhoven
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D028243:Cerebral Amyloid Angiopathy, Familial / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry / Q000473:pathology; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010375:Pedigree; D012150:Polymorphism, Restriction Fragment Length; D053764:Presenilin-1; D011877:Radionuclide Imaging
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1