Chronic stress accelerates Alzheimer pathology in mice by hyperactivating mTORC1

In 5xFAD mice, researchers investigated how chronic restraint stress accelerates Alzheimer's disease progression. Chronic stress impaired cortical slow-wave oscillations, induced prefrontal single-neuron hyperactivity, and aggravated cognitive decline. Stressed mice also showed increased amyloid-beta deposition, dystrophic neurites, and reactive gliosis. Molecular profiling revealed that chronic stress suppressed autophagic pathways via selective hyperactivation of mTORC1 signaling rather than AMPK pathways. This mTORC1 activation and autophagy dysfunction preceded visible amyloid accumulation. Chemically activating mTOR worsened autophagic impairment and elevated amyloid-beta 42 levels. Conversely, pharmacological inhibition of mTORC1 using EN6 restored autophagic function, decreased BACE1 abundance and amyloid burden, calmed neuroinflammation, and rescued both network synchronization and cognitive deficits.