Autophagy Enhancer Carbamazepine Alleviates Memory Deficits and Cerebral Amyloid-β Pathology in a Mouse Model of Alzheimer's Disease

Lixi      Li; Sufang      Zhang; Xin      Zhang; Ting      Li; Yu      Tang; Hui      Liu; Wendi      Yang; Weidong      Le

Abstract

Autophagy plays an important role in Alzheimer's disease (AD). It has been reported that autophagic flux is altered in patients with AD, and application of the autophagy enhancer rapamycin may alleviate the cognitive impairment and amyloid-β (Aβ) neuropathology in transgenic animal model of AD. Since rapamycin is also an immune suppressor, there is a concern that long-term use of rapamycin may bring severe unwanted side effects. The aim of this study is to test if carbamazepine (CBZ), an anti-epileptic drug that has a potent autophagy enhancement effect, has anti-AD effects in APP^swe/PS1^deltaE9 transgenic mice model of AD. We found that APP^swe/PS1^deltaE9 mice display increased autophagic activity accompanied by decreased mTOR activity. After three months treatment with CBZ in the APP^swe/PS1^deltaE9 mice, we demonstrated that the spatial learning and memory deficits in these mice are significantly alleviated. We also documented that the cerebral amyloid plaque burden and Aβ₄₂ levels in these mice are significantly reduced. Furthermore, we showed that CBZ significantly enhances the autophagic flux in the APP^swe/PS1^deltaE9 mice which is unlikely via mTOR-dependent autophagy pathway. These data suggest that long-term CBZ treatment may have a protective effect in AD mouse model possibly through enhancing the autophagic flux.

Keywords: Amyloid-β, Alzheimer's disease, autophagy, carbamazepine, mTOR pathway, spatial memory

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