Cellular response to β-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics.

Abstract

β-Amyloid (Aβ) is a specific pathological hallmark of Alzheimer's disease (AD). Because of its neurotoxicity, AD patients exhibit multiple brain dysfunctions. Disease-modifying therapy (DMT) is the central concept in the development of AD therapeutics today, and most DMT drugs that are currently in clinical trials are anti-Aβ drugs, such as aducanumab and lecanemab. Therefore, understanding Aβ's neurotoxic mechanism is crucial for Aβ-targeted drug development. Despite its total length of only a few dozen amino acids, Aβ is incredibly diverse. In addition to the well-known Aβ1-42 , N-terminally truncated, glutaminyl cyclase (QC) catalyzed, and pyroglutamate-modified Aβ (pEAβ) is also highly amyloidogenic and far more cytotoxic. The extracellular monomeric Aβx-42 (x=1-11) initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor-coupled signal pathways. These signal cascades further influence many cellular metabolism-related processes, such as gene expression, cell cycle, and cell fate, and ultimately cause severe neural cell damage. However, endogenous cellular anti-Aβ defense processes always accompany the Aβ-induced microenvironment alterations. Aβ-cleaving endopeptidases, Aβ-degrading ubiquitin-proteasome system (UPS), and Aβ-engulfing glial cell immune responses are all essential self-defense mechanisms that we can leverage to develop new drugs. This review discusses some of the most recent advances in understanding Aβ-centric AD mechanisms and suggests prospects for promising anti-Aβ strategies.