| First Author | Yu ZY | Year | 2022 |
| Journal | J Neurochem | Volume | 161 |
| Issue | 3 | Pages | 293-307 |
| PubMed ID | 35244207 | Mgi Jnum | J:349610 |
| Mgi Id | MGI:7330290 | Doi | 10.1111/jnc.15603 |
| Citation | Yu ZY, et al. (2022) Inhibiting alpha1-adrenergic receptor signaling pathway ameliorates AD-type pathologies and behavioral deficits in APPswe/PS1 mouse model. J Neurochem 161(3):293-307 |
| abstractText | The role of alpha1 adrenergic receptors (alpha1-ARs) signaling pathway in the pathogenesis of Alzheimer's disease (AD) has rarely been investigated. Clarifying the pathophysiological functions of alpha1-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 (alpha1-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. alpha1-ARs knockdown mice exhibited improved behavioral performances in comparison with control mice. alpha1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Abeta species, compact and total Abeta plaques, than control mice. alpha1-ARs inhibitor terazosin substantially reduced Abeta 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 alpha1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3beta, thus reducing Abeta production. This study indicates that inhibition of alpha1-ARs signaling pathway might represent a promising therapeutic strategy for AD. |
