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

Nanomedicine : Nanotechnology, Biology, and Medicine
Abhijith G KarkisavalRatnesh Lal

Abstract

Aβ deposition is a pathological hallmark of Alzheimer's disease (AD). Besides the full-length amyloid forming peptides (Aβ1-40 and Aβ1-42), biochemical analyses of brain deposits have identified a variety of N- and C-terminally truncated Aβ variants in sporadic and familial AD patients. However, their relevance for AD pathogenesis remains largely understudied. We demonstrate that Aβ4-42 exhibits a high tendency to form β-sheet structures leading to fast self-aggregation and formation of oligomeric assemblies. Atomic force microscopy and electrophysiological studies reveal that Aβ4-42 forms highly stable ion channels in lipid membranes. These channels that are blocked by monoclonal antibodies specifically recognizing the N-terminus of Aβ4-42. An Aβ variant with a double truncation at phenylalanine-4 and leucine 34, (Aβ4-34), 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 Aβ species in AD pathophysiology.

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