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.

• Authors: Jitika Rajpoot, Elliot J Crooks, Brandon A Irizarry, Ashley Amundson, William E Van Nostrand, Steven O Smith
• Journal: Biochemistry (Biochemistry) Vol. 61 Issue 12 Pg. 1181-1198 (06 21 2022) ISSN: 1520-4995 [Electronic] United States
• PMID: 35666749 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Peptide Fragments

Topics

• Alzheimer Disease
• Amyloid
• Amyloid beta-Peptides (chemistry, genetics)
• Cerebral Amyloid Angiopathy (genetics, pathology)
• Humans
• Iowa
• Peptide Fragments (chemistry, genetics)
• Plaque, Amyloid (pathology)