Ion channel formation by N-terminally truncated Aβ (4-42): relevance for the pathogenesis of Alzheimer's disease

A beta deposition is a pathological hallmark of Alzheimer's disease (AD). Besides the full-length amyloid forming peptides (A beta 1-40 and A beta 1-42), biochemical analyses of brain deposits have identified a variety of Nand C-terminally truncated A beta variants in sporadic and familial AD patients. However, their relevance for AD pathogenesis remains largely understudied. We demonstrate that A beta 4-42 exhibits a high tendency to form beta-sheet structures leading to fast self-aggregation and formation of oligomeric assemblies. Atomic force microscopy and electrophysiological studies reveal that A beta 4-42 forms highly stable ion channels in lipid membranes. These channels that are blocked by monoclonal antibodies specifically recognizing the N-terminus of A beta 4-42. An A beta variant with a double truncation at phenylalanine-4 and leucine 34, (A beta 4-34), exhibits unstable channel formation capability. Taken together the results presented herein highlight the potential benefit of C-terminal proteolytic cleavage and further support an important pathogenic role for N-truncated A beta species in AD pathophysiology. (c) 2020 Elsevier Inc. All rights reserved.