Inhibiting α1‐adrenergic receptor signaling pathway ameliorates AD‐type pathologies and behavioral deficits in APPswe/PS1 mouse model

Journal of Neurochemistry - Tập 161 Số 3 - Trang 293-307 - 2022
Zhongyuan Yu1, Xu Yi1, Ye‐Ran Wang1, Gui‐Hua Zeng1, Cheng‐Rong Tan1, Yuan Cheng1, Pu‐Yang Sun1, Бо Лю1, Yan‐Jiang Wang2,3,1, Yuhui Liu1
1Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
2Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
3Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China

Tóm tắt

AbstractThe role of α1 adrenergic receptors (α1‐ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of α1‐ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic targets of AD. This study included 2 arms of in vivo investigations: 1) 6‐month‐old female APPswe/PS1 mice were intravenously treated with AAV‐PHP.eB‐shRNA (α1‐ARs)‐GFP or AAV‐PHP.eB‐GFP for 3 months. 2) 3‐month‐old female APPswe/PS1 mice were daily treated with 0.5 mg/kg terazosin or an equal volume of saline for 6 months. SH‐SY5Y cell lines bearing human amyloid precursor protein were treated with terazosin or saline for investigating possible mechanisms. α1‐ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. α1‐ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total Aβ plaques, than control mice. α1‐ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction et al., and rescued behavioral deficits in APPswe/PS1 mice. In vitro investigation demonstrated that α1‐ARs inhibition down‐regulated BACE1 expression, and promoted ser9 phosphorylation of GSK‐3β, thus reducing Aβ production. This study indicates that inhibition of α1‐ARs signaling pathway might represent a promising therapeutic strategy for AD.image

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Thông tin xuất bản

Journal of Neurochemistry

Tập 161 Số 3

293-307

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