Repurposing beta3-adrenergic receptor agonists for Alzheimer’s disease: Beneficial effects on recognition memory and amyloid pathology in a mouse model

Abstract

Old age, the most important risk factor for Alzheimer's disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through β3-adrenergic receptor (β3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a β3AR agonist could exert benefits in AD as well.Here, we show that β3AR agonist administration (CL-316,243, 1 mg/kg/day i.p., from 15 to 16 months of age) decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a β3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old).Locomotion, anxiety and tau pathology were not modified. Finally, insoluble Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice.Overall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy.

Suppression of estrogen receptor beta classical genomic activity enhances systemic and adipose-specific response to chronic beta-3 adrenergic receptor (β3AR) stimulation

“…However, modest sex-specific genotype effects were observed, suggesting that lack of ERβ DBD did affect CL’s glucose regulatory role, at least in a minor way. It is well established ( Kuk and Ardern, 2010 ; Tournissac et al, 2020 ), and we recently confirmed, that males are more susceptible to obesity-induced metabolic dysfunction. Recently, we demonstrated that CL effectively improves insulin resistance and adipose tissue metabolism in males ( Queathem et al, 2021 ).…”

“…Recent studies have shown that combining CL with antidiabetic drugs (e.g., liraglutide) ( Decara et al, 2018 ) has additional benefits. While β3ARs are expressed in several tissues (e.g., WAT and brown adipose tissue (BAT) ( Evans et al, 1996 ; Monjo et al, 2005 ; Baskin et al, 2018 ; Tournissac et al, 2020 ), kidney ( Procino et al, 2016 ), bladder ( Procino et al, 2016 ), colon ( Evans et al, 1996 ; Chamberlain et al, 1999 ), stomach ( Evans et al, 1996 ), prostate ( Chamberlain et al, 1999 ), gallbladder ( Baskin et al, 2018 ), skeletal myocytes ( Chamberlain et al, 1999 ), and cardiomyocytes ( Chamberlain et al, 1999 ; Balligand, 2017 ; Machuki et al, 2018 )), they have a uniquely high level of expression on adipocytes ( Evans et al, 1996 ; Chamberlain et al, 1999 ). Therefore, the beneficial effects of CL have largely been attributed to its adipocyte-specific effects.…”

β3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations

“…In contrast, other models of colonic disorders have shown neuronal loss or different alterations in neuronal subpopulations [36,42,43]. Our key finding that hyperoxia did not reduce the total number of neurons strongly suggests that β3-AR activation exerts a neuroprotective effect, not substantially preventing cell loss, as previously demonstrated in a model of retinal damage [44,45], but rather by improving the maturation process. Conceivably, the β3-AR agonist BRL37344 kept the neurochemical coding of the myenteric plexus almost unchanged by uncoupling its developmental process from the adverse effect of hyperoxia.…”

The novel anti-colitic effect of β-adrenergic receptors via modulation of PS1/BACE-1/Aβ axis and NOTCH signaling in an ulcerative colitis model

“…Although no studies have reported a relation between β3-AR agonists and PS1 or BACE-1, the beneficial role of a β3-AR agonist against Aβ was reported in a model of AD, where it helped to avert the Aβ-induced memory loss, whereas the effect of a β2 agonist was more limited (Gibbs, 2015). Previous studies, both these co-authors and others, also reached the same conclusion, where activation of β3-AR, but not β2, reduced Aβ and its production and prevented the associated memory loss in an AD model (Gibbs et al, 2010;Tournissac et al, 2021); these facts support our findings. The failure of β2-AR agonists to mediate similar effects may be owed to the binding of β2-AR to Aβ leading to its dysfunction and degeneration (Wang et al, 2011), a finding that can explain the effect of the β2-AR blocker carvedilol.…”

“…Amyloidosis is known to accompany AD centrally, but no direct role in ulcerative colitis has yet been reported. Nevertheless, the association between dementia and patients with IBD (Zhang et al, 2021) and the beneficial role of β3 agonism for AD (Tournissac et al, 2021) has been recently highlighted. In addition, earlier studies reported that Aβ or its precursor was present in the enteric neurons of patients with AD (Shankle et al, 1993;Puig et al, 2015;Yi et al, 2017).…”