Aerobic Exercise Improves Cognitive Recovery in Mice with Chronic Cerebral Hypoperfusion by Modulating the Annexin-A1-MAPK Axis and Astrocyte Polarization

Vascular cognitive impairment and dementia (VCID), resulting from chronic cerebral hypoperfusion, represent the second most prevalent form of dementia globally. Aerobic exercise is widely acknowledged as an effective intervention for various cognitive disorders. This study utilized a bilateral common carotid artery stenosis (BCAS) model to investigate whether aerobic exercise promotes cognitive recovery through the Annexin-A1 (ANXA1)/mitogen-activated protein kinase (MAPK) axis in BCAS mice. Our findings demonstrate that aerobic exercise improved spatial memory in BCAS mice by enhancing white matter (WM) integrity and hippocampal function. WM integrity was confirmed through Luxol Fast Blue (LFB) staining and protein assays. Additionally, aerobic exercise mitigated BCAS-induced long-term potentiation (LTP) decay and upregulated hippocampal expression of key synaptic proteins, including N-methyl-D-aspartate receptor subunits NR2B and NR1, vesicular glutamate transporter 1 (vGluT1), and the synaptic scaffolding protein postsynaptic density protein 95 (PSD95). Furthermore, aerobic exercise enhanced the expression of the anti-inflammatory mediator ANXA1 through exosome secretion while simultaneously suppressing the MAPK signaling pathway. These molecular changes were associated with increased astrocyte proliferation and the polarization of astrocytes toward the A2 phenotype. These findings were further validated using an in vitro co-culture model of astrocytes (U251) and neurons (HT22). In summary, our study demonstrates that aerobic exercise improves WM integrity and hippocampal function by modulating the ANXA1/MAPK axis following astrocyte polarization. Thus, aerobic exercise emerges as a promising intervention for promoting functional recovery in VCID.