Behavioural Brain Research · May 23, 2025

Physical exercise mitigates the cognitive impairments by promoting ER-phagy in mice model of Alzheimer's disease

By Li L, Li S, Cai L et al.

Alzheimer's disease (AD) is the primary cause of dementia in older individuals, exhibiting an increasing incidence worldwide. Endoplasmic reticulum (ER) quality control has been receiving attention in the pathology of AD. The accumulation of misfolded proteins in the ER will activates the unfolded protein response (UPR), leading to cellular apoptosis. Using a mouse model of 5xFAD, we found that physical exercise (PE) promoted the clearance of ER fragments and inhibited the ER stress via ER autophagy (ER - Phagy). As a result, physical exercise reduced Aβ deposition, inhibited the neuronal apoptosis, ameliorated the emotional and cognitive impairments. Mechanistically, these PE related effects may be linked to the increased FAM134B, an ER-Phagy receptor, by up-regulating neuronal progranulin (Pgrn). Recombinant Pgrn injection could mimic the protective effects of PE, whereas down-regulation of Pgrn could abolish the PE-associated protection. Our findings indicate that physical exercise, as a readily accessible lifestyle intervention, holds significant potential for preventing diseases related to the global aging population.

doi.org/10.1016/j.bbr.2025.115650PubMed 40414310Interventions