{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:01:48Z","timestamp":1790607708582,"version":"4.1.0"},"reference-count":49,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2010level mechanisms linking chronic stress to accelerated AD pathogenesis and evaluated the therapeutic potential of precise mTORC1 targeting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A chronic restraint stress (CRS) paradigm was established in 5xFAD mice. Multi\u2010scale neurofunctional and histopathological alterations were deconstructed using behavioral profiling, wide\u2010field and two\u2010photon calcium imaging, immunofluorescence, and bulk RNA\u2010sequencing. Pharmacological intervention was conducted using the specific mTORC1 inhibitor EN6.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CRS severely impaired cortical slow\u2010wave oscillations and induced aberrant prefrontal single\u2010neuron hyperactivity, exacerbating cognitive decline. These network deficits were accompanied by accelerated AD hallmarks, including elevated A\u03b2 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\u2010course analysis showed that mTORC1 activation and autophagy\u2010related abnormalities preceded overt A\u03b2 accumulation, while pharmacological mTOR activation with MHY1485 further aggravated autophagic impairment and increased A\u03b242 levels. Crucially, targeted mTORC1 inhibition with EN6 ameliorated autophagy\u2010related abnormalities and was associated with reduced BACE1 abundance and CTF\u03b2 generation, together with a diminished global A\u03b2 burden. This microenvironmental stabilization attenuated neuroinflammation, realigned neural networks, and rescued both cognitive and emotional deficits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Chronic stress\u2010induced mTORC1 hyperactivation is associated with autophagic impairment, contributing to macro\u2010circuit desynchronization and accelerated amyloid accumulation. Targeting the mTORC1\u2013autophagy axis represents a potential therapeutic approach to mitigate neural network breakdown and neuropathology in stress\u2010related neurodegenerative conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.71174","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:52:42Z","timestamp":1790607162000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>mTORC1<\/scp>\n                    Activation Links Chronic Stress to Meso\u2010Circuit Desynchronization and Accelerated Amyloid Pathology via Autophagic Dysfunction"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-2328-7066","authenticated-orcid":false,"given":"Yang","family":"Zou","sequence":"first","affiliation":[{"name":"Center for Medical Research The First People's Hospital of Yulin, The Sixth Affiliated Hospital of Guangxi Medical 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