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

Abstract

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.

A pilot dose-finding study of Terazosin in humans

“…On the other hand, our data may have applicability for additional neurodegenerative diseases that also exhibit impaired brain bioenergetics, like those that have reported TZ efficacy in models of Alzheimer's disease 53 , amyotrophic lateral sclerosis 54 , and spinal muscular atrophy. 55 Another limitation is the short duration of this study.…”

“…A limitation of this study is that we used neurologically healthy participants and dose-response relationships, and adverse events may differ in PD patients who have unique biological features. On the other hand, our data may have applicability for additional neurodegenerative diseases that also exhibit impaired brain bioenergetics, like those that have reported TZ efficacy in models of Alzheimer’s disease 53 , amyotrophic lateral sclerosis 54 , and spinal muscular atrophy. 55 Another limitation is the short duration of this study.…”

Disease phenotypic screening in neuron-glia cocultures identifies blockers of inflammatory neurodegeneration

“…However, two of these (doxazosin and alfuzosin, 111 and 112) are relatively specific α 1 -ADR inhibitors, so would not block endogenous neuroprotective activity from β-ADRs while instead inhibiting potentially proinflammatory α 1 -ADRs. 110 , 111 , 112 , 113 The remaining ADR antagonist, labetalol (6), inhibits both α 1 -ADR and β-ADRs, which alongside its low potency may explain its lower protective efficacy (37%). Finally, some ADR modulators were not protective including the α 1 -and β-ADR agonist isoproterenol (83), 114 which is compatible with β-ADRs protecting while α 1 -ADRs are detrimental.…”

Finding Drug Repurposing Candidates for Neurodegenerative Diseases using Zebrafish Behavioral Profiles

“…Comparably, α-adrenergic receptors (αARs) have been extensively linked to cognition as well as glucose metabolism - both part of AD symptomatology (Gannon et al, 2015). αAR antagonists, in particular, have been investigated both in vitro and in vivo as promising therapeutic targets of AD(Karczewski et al, 2018; Katsouri et al, 2013; Yu et al, 2022), and could prove interesting targets for future experiments.…”