N-Truncated Aβ Starting at Position Four-Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer's Disease

The discussion of whether amyloid plaque A beta is a valid drug target to fight Alzheimer's disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid A beta peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate A beta, showed beneficial effects in a phase II trial, supporting the concept that N-truncated A beta is a relevant target for AD therapy. There is long-standing evidence that N-truncated A beta variants are the main variants found in amyloid plaques besides full-length A beta(1-42), t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate A beta(3-42) to AD pathology has been well studied in the past, the potential role of A beta(4-42) has been largely neglected. The present review will therefore focus on A beta(4-42) as a possible drug target based on human and mouse pathology, in vitro and in vivo toxicity, and anti-A beta(4-X) therapeutic effects in preclinical models.

Automated summary

Recent studies on Alzheimer's disease have suggested that N-truncated Aβ may be an effective therapeutic target and warrant further research. While past research has mainly focused on the contribution of N-terminal pyroglutamate Aβ to pathology, the potential role of Aβ(4-42) has been overlooked.