Authors
Hui-Hui Guo, Hai-Ning Ou, Jia-Sui Yu, Zi-Rui Luo, Suk-Yu Yau, Hector Wing-Hong Tsang
Published in
Aging cell. Volume 25. Issue 3. Pages e70447.
Abstract
Protein phosphatase 2A (PP2A) regulates Tau hyperphosphorylation in Alzheimer's disease (AD). This study hypothesized that exercise increases adiponectin levels, activating PP2A to reduce Tau hyperphosphorylation and enhance hippocampal plasticity. The study utilized adiponectin knockout (Adipo-/-) and hippocampal-specific PP2A knockdown (PP2A-KD) in mice with 3-week voluntary running and/or chronic stress to assess changes in Tau phosphorylation, adult neurogenesis, and cognitive performance. Running improved cognitive deficits and reduced Tau hyperphosphorylation in association with increased adiponectin levels and enhanced PP2A activity in stressed mice. Adiponectin deficiency impaired cognitive performance, increased Tau phosphorylation, and decreased PP2A activity. Mechanistically, adiponectin is dispensable for running to increase PP2A activity, reduce Tau hyperphosphorylation, and restore hippocampal neurogenesis, leading to cognitive improvement. Hippocampal-specific PP2A knockdown diminished the beneficial effects of running, indicating that PP2A is downstream of adiponectin's action. This study provides mechanistic insights into how exercise reduces AD-like neuropathology, emphasizing the critical role of the adiponectin-PP2A pathway in mitigating Tau hyperphosphorylation and suggesting a potential therapeutic target for AD through modulation of this pathway.
PMID:
41841751
Bibliographic data and abstract were imported from PubMed on 17 Sep 2026.
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