Insights into Cerebral Amyloid Angiopathy Type 1 and Type 2 from Comparisons of the Fibrillar Assembly and Stability of the Aβ40-Iowa and Aβ40-Dutch Peptides

Abstract

Two distinct diseases are associated with the deposition of fibrillar amyloid-β (Aβ) peptides in the human brain in an age-dependent fashion. Alzheimer’s disease is primarily associated with parenchymal plaque deposition of Aβ42, while cerebral amyloid angiopathy (CAA) is associated with amyloid formation of predominantly Aβ40 in the cerebral vasculature. In addition, familial mutations at positions 22 and 23 of the Aβ sequence can enhance vascular deposition in the two major subtypes of CAA. The E22Q (Dutch) mutation is associated with CAA type 2, while the D23N (Iowa) mutation is associated with CAA type 1. Here we investigate differences in the formation and structure of fibrils of these mutant Aβ peptides in vitro to gain insights into their biochemical and physiological differences in the brain. Using Fourier transform infrared and nuclear magnetic resonance spectroscopy, we measure the relative propensities of Aβ40-Dutch and Aβ40-Iowa to form antiparallel structure and compare these propensities to those of the wild-type Aβ40 and Aβ42 isoforms. We find that both Aβ40-Dutch and Aβ40-Iowa have strong propensities to form antiparallel β-hairpins in the first step of the fibrillization process. However, there is a marked difference in the ability of these peptides to form elongated antiparallel structures. Importantly, we find marked differences in the stability of the protofibril or fibril states formed by the four Aβ peptides. We discuss these differences with respect to the mechanisms of Aβ fibril formation in CAA.

Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments

“…Aβ-affected vessels represent a pathological basis for developing cerebrovascular disorders like micro-and macro-hemorrhage and micro-and macroinfarction. 37 AD and CAA have overlapping pathology, sharing genetic polymorphisms in ApoE (apolipoprotein E), PS1 (presenilin 1), α1-antichymotrypsin, and neprilysin. [38][39][40] In particular, possession of the Apoε4 allele is associated with CAA severity.…”

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

“…This process is marked by the reactive gliosis surrounding amyloid deposits in the brain, involving multiple distinct species of Aβ fibrils. For example, it involves the Aβ42 fibrils primarily comprising the hallmark parenchymal plaques in AD and the Aβ40 fibrils primarily associated with the vascular amyloid deposits observed in CAA [ 2 , 3 , 4 , 11 , 12 , 89 ]. As observed in several animal models and AD patients, chronic glial activation and pro-inflammatory cytokine and chemokine production stimulate neurodegenerative processes [ 87 , 90 , 91 , 92 ].…”

An electrostatic cluster guides Aβ40 fibril formation in cerebral amyloid angiopathy

“…There is a wide range of data supporting the rapid formation of β-hairpin intermediates on the pathway to Aβ fibrils 49 , providing a potential explanation for their inclusion in population B. Monomeric Aβ spontaneously forms β-hairpins 50 . However, we previously found that the Aβ40-Dutch peptide, and other fCAA mutants at positions E22 and D23, form β-hairpin structures much more rapidly than wild-type Aβ40 50 . The peptides may then layer upon pre-formed fibrils having the linear structure of population B.…”

“…This structural polymorphism may originate from β-hairpins associated with the outer densities as described by Ghosh et al 29 , or from the association of metal ions or proteins to the Nterminus in cellular environments. There is a wide range of data supporting the rapid formation of βhairpin intermediates on the pathway to Aβ fibrils 49 , providing a potential explanation for their inclusion in population B. Monomeric Aβ spontaneously forms β-hairpins 50 . However, we previously found that the Aβ40-Dutch peptide, and other fCAA mutants at positions E22 and D23, form β-hairpin structures much more rapidly than wild-type Aβ40 50 .…”