title: Cerebral vascular amyloid seeds drive amyloid β-protein fibril assembly with a distinct anti-parallel structure.
abstract: Cerebrovascular accumulation of amyloid β-protein (Aβ), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease. Familial Aβ mutations, such as Dutch-E22Q and Iowa-D23N, can cause severe cerebrovascular accumulation of amyloid that serves as a potent driver of vascular cognitive impairment and dementia. The distinctive features of vascular amyloid that underlie its unique pathological properties remain unknown. Here, we use transgenic mouse models producing CAA mutants (Tg-SwDI) or overproducing human wild-type Aβ (Tg2576) to demonstrate that CAA-mutant vascular amyloid influences wild-type Aβ deposition in brain. We also show isolated microvascular amyloid seeds from Tg-SwDI mice drive assembly of human wild-type Aβ into distinct anti-parallel β-sheet fibrils. These findings indicate that cerebrovascular amyloid can serve as an effective scaffold to promote rapid assembly and strong deposition of Aβ into a unique structure that likely contributes to its distinctive pathology.
authors.affiliation: Departments of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Ziao
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Dass
authors.affiliation: Departments of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: AnnMarie E
authors.initials: AE
authors.lastname: Kotarba
authors.affiliation: Departments of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Judianne
authors.initials: J
authors.lastname: Davis
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Steven O
authors.identifier: 0000-0003-1861-7159
authors.initials: SO
authors.lastname: Smith
authors.affiliation: Departments of Neurosurgery and Medicine, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000686:Amyloidosis / Q000473:pathology; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor