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

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 Aβ 1‐42 , N‐terminally truncated, glutaminyl cyclase (QC) catalyzed, and pyroglutamate‐modified Aβ (pEAβ) is also highly amyloidogenic and far more cytotoxic. The extracellular monomeric Aβ x‐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.

Abstract licence: CC BY-NC-ND

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