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

The 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. Inhibition of the α1 adrenergic receptors (α1‐ARs) signaling pathway ameliorates behavioral deficits and Alzheimer's disease (AD)‐type pathologies, including deposition of amyloid‐beta (Aβ), tau hyperphosphorylation, neuroinflammation, and neurodegeneration. The protection of α1‐ARs inhibition against AD might be associated with its effects on BACE1 inhibition and ser9 phosphorylation of GSK‐3β. This study indicates that inhibition of α1‐ARs signaling pathway might represent a promising therapeutic strategy for AD.