ATTENUATION OF AKT-MTORC1-P70S6K ACTIVATION, TAU PHOSPHORYLATION AND INFLAMMATION IN THE CEREBRAL CORTEX INFARCTED BY PHOTOCHEMICALLY INDUCED THROMBOSIS BY REHABILITATION TRAINING

Abstract

Although stroke elicits progressive cognitive decline and is a major cause of dementia, molecular interplay between stroke and Alzheimer's disease (AD) pathology has not been fully elucidated. Furthermore, studies on the effects of post-stroke rehabilitation on AD pathology are limited. The care of animals and a protocol approved by the Institutional Animal Care and Handling Committee. Sprague-Dawley rats were randomly assigned to rehabilitation group (RG) and sedentary control group (SC) following photothrombotic infarction in the dominant side of sensorimotor cortex. RG received 4-weeks of task-specific rehabilitation once daily by single pellet reaching training (SPRT). Cortical expression levels of proteins related to tau modification and inflammation were evaluated on post-stroke day (PSD) 1 and 28. The expression levels of acetyl-tau, phosphorylated-tau at Ser262(p-tauS262) and Ser202/Thr205 (p-tau202/205) and truncated tau on PSD1 were significantly higher in infarcted cortex (ipsilateral) than the paired non-ischemic cortex (contralateral), whereas p-tauS396 levels was comparable. The positive feedback loop of Akt-mTORC2 (p-Sin1) and concurrent activation of mTORC1-p70S6K pathway in ipsilateral sides on PSD1 were significantly greater, whereas the expression levels of p-AMPK, GSK3β activity, Sirt1 and brain-derived neurotrophic factor were significantly lower than in the paired contralateral sides. The acute increase of cyclooxygenase 2 (COX-2) levels was also observed. The rehabilitation by SPRT for 4 weeks significantly attenuated the tau phosphorylation and activation of Akt-mTORC1-p70S6K pathway in ipsilateral cortex of RG, as compared to those in ipsilateral cortex of SC, which concurred with improvement of functional motor performance but not memory. In addition, the levels of ipsilateral p-AMPK and COX-2 of RG was significantly lower than those of SC, whereas the ipsilateral GSK3β activity and acetyl tau levels of RG were comparable to those of SC. Photothrombotic cortical infarction was found to induce cortical tau modification through the Akt-mTORC1-p70S6K activation, and to downregulate the expression of AMPK-related proteins. Task-specific rehabilitation for 4 weeks greatly improved motor function, but not memory, and suppressed p-tau expression and neuroinflammation. These results indicated that rehabilitation training may attenuate the acute pathologic changes related to tau modification and inflammation after cortical ischemic damage.