Interaction between Angiotensin Receptor and β-Adrenergic Receptor Regulates the Production of Amyloid β-Protein

Abstract

Alzheimer's disease (AD) is characterized by the formation of extracellular amyloid plaques containing the amyloid β-protein (Aβ) within the parenchyma of the brain. Aβ is considered to be the key pathogenic factor of AD. Recently, we showed that Angiotensin II type 1 receptor (AT 1 R), which regulates blood pressure, is involved in Aβ production, and that telmisartan (Telm), which is an angiotensin II receptor blocker (ARB), increased Aβ production via AT 1 R. However, the precise mechanism underlying how AT 1 R is involved in Aβ production is unknown. Interestingly, AT 1 R, a G protein-coupled receptor, was strongly suggested to be involved in signal transduction by heterodimerization with β 2-adrenergic receptor (β 2-AR), which is also shown to be involved in Aβ generation. Therefore, in this study, we aimed to clarify whether the interaction between AT 1 R and β 2-AR is involved in the regulation of Aβ production. To address this, we analyzed whether the increase in Aβ production by Telm treatment is affected by β-AR antagonist using fibroblasts overexpressing amyloid precursor protein (APP). We found that the increase in Aβ production by Telm treatment was decreased by the treatment of β 2-AR selective antagonist ICI-118551 more strongly than the treatment of β 1-AR selective antagonists. Furthermore, deficiency of AT 1 R abolished the effect of β 2-AR antagonist on the stimulation of Aβ production caused by Telm. Taken together, the interaction between AT 1 R and β 2-AR is likely to be involved in Aβ production.

RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus

“…Some studies have shown that they improve cognitive deficits in AD transgenic mice, prevent an increase of Αβ, phosphorylated tau and neprilysin, and decreased levels of TNF-α [ 109 – 114 ]. In contrast, other studies do not support use of candesartan or telmisartan in AD or PD due to limited benefits in animal models [ 115 – 117 ].…”