mTORC1 Activation Links Chronic Stress to Meso‐Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction

Abstract

ABSTRACT Background Although depression is a potent risk factor for Alzheimer's disease (AD), the underlying causal mechanisms remain unclear. This study investigated the molecular and circuit‐level mechanisms linking chronic stress to accelerated AD pathogenesis and evaluated the therapeutic potential of precise mTORC1 targeting. Methods A chronic restraint stress (CRS) paradigm was established in 5xFAD mice. Multi‐scale neurofunctional and histopathological alterations were deconstructed using behavioral profiling, wide‐field and two‐photon calcium imaging, immunofluorescence, and bulk RNA‐sequencing. Pharmacological intervention was conducted using the specific mTORC1 inhibitor EN6. Results CRS severely impaired cortical slow‐wave oscillations and induced aberrant prefrontal single‐neuron hyperactivity, exacerbating cognitive decline. These network deficits were accompanied by accelerated AD hallmarks, including elevated Aβ deposition, dystrophic neurite aggravation, and reactive gliosis. Mechanistically, transcriptomic profiling and biochemical validation revealed that chronic stress suppresses autophagic pathways via selective hyperactivation of mTORC1 signaling rather than the AMPK pathway. Time‐course analysis showed that mTORC1 activation and autophagy‐related abnormalities preceded overt Aβ accumulation, while pharmacological mTOR activation with MHY1485 further aggravated autophagic impairment and increased Aβ42 levels. Crucially, targeted mTORC1 inhibition with EN6 ameliorated autophagy‐related abnormalities and was associated with reduced BACE1 abundance and CTFβ generation, together with a diminished global Aβ burden. This microenvironmental stabilization attenuated neuroinflammation, realigned neural networks, and rescued both cognitive and emotional deficits. Conclusion Chronic stress‐induced mTORC1 hyperactivation is associated with autophagic impairment, contributing to macro‐circuit desynchronization and accelerated amyloid accumulation. Targeting the mTORC1–autophagy axis represents a potential therapeutic approach to mitigate neural network breakdown and neuropathology in stress‐related neurodegenerative conditions.