Abstract
Cerebral amyloid angiopathy (CAA) is a vascular disorder that primarily involves deposition of the 40-residue-long β-amyloid peptide (Aβ40) in and along small blood vessels of the brain. CAA is often associated with Alzheimer's disease (AD), which is characterized by amyloid plaques in the brain parenchyma enriched in the Aβ42 peptide. Several recent studies have suggested a structural origin that underlies the differences between the vascular amyloid deposits in CAA and the parenchymal plaques in AD. We previously have found that amyloid fibrils in vascular amyloid contain antiparallel β-sheet, whereas previous studies by other researchers have reported parallel β-sheet in fibrils from parenchymal amyloid. Using X-ray fluorescence microscopy, here we found that copper strongly co-localizes with vascular amyloid in human sporadic CAA and familial Iowa-type CAA brains compared with control brain blood vessels lacking amyloid deposits. We show that binding of Cu(II) ions to antiparallel fibrils can block the conversion of these fibrils to the more stable parallel, in-register conformation and enhances their ability to serve as templates for seeded growth. These results provide an explanation for how thermodynamically less stable antiparallel fibrils may form amyloid in or on cerebral vessels by using Cu(II) as a structural cofactor.
Highlights
B-Amyloid peptide (Ab) fibrillar assembly and deposition in brain parenchymal plaques is a hallmark of Alzheimer’s disease (AD), a prevalent neurodegenerative disorder in the elderly population [1]
The studies below focus on Ab40-Iowa because it has an enhanced ability to form vascular amyloid in human brain, which may be related to its unique anti-parallel fibril structure that is known to form in solution
The relative amount of copper bound to Ab was determined by normalizing to the protein content in the vessels, which was separately estimated by FTIR microspectroscopy (Fig. 1G)
Summary
B-Amyloid peptide (Ab) fibrillar assembly and deposition in brain parenchymal plaques is a hallmark of Alzheimer’s disease (AD), a prevalent neurodegenerative disorder in the elderly population [1]. The Ab peptide, a major component of the amyloid deposits in both parenchymal and vascular plaques, is generated by proteolytic cleavage of the transmembrane region of the amyloid precursor protein (APP). Subsequent cleavage by g-secretase at the C-terminal end of the Ab domain of APP releases the Ab peptide. Two prominent mutations are the Iowa-type (D23N) and Dutch-type (E22Q) mutations [9, 10] Both mutant peptides have an acidic residue substituted with an uncharged amine that may lead to structural differences originating from electrostatic interactions. Structure-sensitive dyes have exhibited differences in binding to amyloid deposited from WT and familial mutant Ab peptides [11]. Together these findings point toward a structural difference between parenchymal and vascular amyloid. The findings that Ab40-Iowa fibrils preferentially form on cerebral blood vessels [18], are linked to severe CAA symptoms in humans [9], and can form a novel anti-parallel structure [15] suggest a causal relationship between Ab fibril structure and clinical pathology
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