An electrostatic cluster guides Abeta fibril formation in cerebral amyloid angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar A{beta} peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimers disease (AD). We investigate the structure of human-derived A{beta}40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro A{beta}40 fibril structures. One population has an ordered N-terminal fold comprised of two {beta}-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations guide fibril formation.