Inhibiting α1-adrenergic Receptor Signaling Pathway Ameliorates Alzheimer’s Disease Type Pathologies and Behavioral Deficits in an AD Mouse Model

Abstract

Background The role of α1 adrenergic receptors (α1-ARs) signaling pathway in the pathogenesis of Alzheimer’s disease (AD) has rarely been investigated. Clarifying pathophysiological functions of α1-ARs in the AD brain is helpful for better understanding the pathogenesis and screening novel therapeutic target of AD. Methods 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 (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 equal saline for 6 months. SH-SY5Y cell lines bearing human Amyloid precurssor protein were treated with terazosin or saline for investigating possible mechanisms. Results α1-ARs knockdown mice exhibited improved behavioral performances than control mice. α1-ARs knockdown mice had significantly lower brain amyloid burden, as reflected by soluble Aβ species, compact and total plaques, than control mice. The α1-ARs inhibitor terazosin substantially reduced Aβ deposition, attenuated downstream pathologies including Tau hyperphosphorylation, glial activation, neuronal loss, synaptic dysfunction, and rescued behavioral deficits of APPswe/PS1 mice. In vitro investigation demonstrated that α1-ARs inhibition down-regulated BACE1 expression, and promoted ser9 phosphorylation of GSK-3β, thus reduced Aβ production. Conclusions This study indicates that inhibition of α1-ARs signaling pathway might represent a promising therapeutic strategy for AD.

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“…124 Additionally, knockdown of α1-adrenergic receptors lessened brain amyloid burden and specifically the α1-adrenergic receptor inhibitor, terazosin, significantly decreased Aβ deposition and attenuated hyperphosphorylation of tau, glial activation, neuronal death, and synaptic dysfunction. 124 It has been found that the expression of α1adrenergic receptors is preserved in the cerebrovasculature within the aging population and in individuals that have CAA, further supporting the feasibility of using α1-adrenergic antagonists to combat dementia related vascular pathology. 125 Not many studies have investigated how drugs that target the α2-adrenergic system affect AD pathology.…”

“…Tamsulosin, another antagonist of the α1‐adrenergic receptor, has recently been found to improve age‐related memory impairment in rats due to increased hippocampal neurogenesis and prevention of apoptosis within the hippocampus 123 . An even more recent study demonstrated that knockdown of α1‐adrenergic receptors within APP/PS1 AD mice improved performances on y‐maze, open field test, Morris water maze, and elevated plus maze 124 . Additionally, knockdown of α1‐adrenergic receptors lessened brain amyloid burden and specifically the α1‐adrenergic receptor inhibitor, terazosin, significantly decreased Aβ deposition and attenuated hyperphosphorylation of tau, glial activation, neuronal death, and synaptic dysfunction 124 .…”

“…An even more recent study demonstrated that knockdown of α1‐adrenergic receptors within APP/PS1 AD mice improved performances on y‐maze, open field test, Morris water maze, and elevated plus maze 124 . Additionally, knockdown of α1‐adrenergic receptors lessened brain amyloid burden and specifically the α1‐adrenergic receptor inhibitor, terazosin, significantly decreased Aβ deposition and attenuated hyperphosphorylation of tau, glial activation, neuronal death, and synaptic dysfunction 124 . It has been found that the expression of α1‐adrenergic receptors is preserved in the cerebrovasculature within the aging population and in individuals that have CAA, further supporting the feasibility of using α1‐adrenergic antagonists to combat dementia related vascular pathology 125 .…”