Adaptive-to-maladaptive IRE1α signaling as a driver of amyloidogenic APP processing in Alzheimer's disease.

Alzheimer's disease (AD) is increasingly recognized as a disorder of proteostatic failure characterized by progressive disruption of neuronal protein quality control, culminating in amyloid-β (Aβ) accumulation and synaptic dysfunction. Chronic activation of the endoplasmic reticulum (ER) stress response represents one of the earliest molecular alterations detected in vulnerable brain regions and correlates with Braak progression before overt plaque deposition. Inositol-requiring enzyme 1 alpha (IRE1α), the most evolutionarily conserved sensor of the unfolded protein response (UPR), functions as a signaling rheostat within this network through its divergent downstream outputs. Under moderate proteotoxic stress, adaptive IRE1α- X-box binding protein 1 (XBP1) signaling supports ER proteostasis, preserves amyloid precursor protein (APP) quality control, and favors non-amyloidogenic α-secretase processing. Persistent ER stress, however, drives sustained IRE1α hyperactivation and engages regulated IRE1α-dependent decay (RIDD), which destabilizes microRNA (miRNA) networks that normally constrain beta-site APP-cleaving enzyme 1 (BACE1) expression, thereby favoring amyloidogenic APP processing. Accumulating evidence suggests that aging progressively compromises ER proteostatic capacity, thereby redirecting IRE1α signaling away from adaptive XBP1s-mediated responses toward a predominantly RIDD-driven state. This shift may reinforce a self-sustaining cycle in which accumulating Aβ further amplifies ER stress signaling. Here, we examine how dynamic changes in IRE1α signaling bias contribute to amyloidogenic progression in AD and consider whether selective modulation of adaptive versus maladaptive IRE1α outputs may offer stage-dependent therapeutic benefit.