Repurposing beta-3 adrenergic receptor agonists for Alzheimer’s disease: beneficial effects in a mouse model

Abstract

Background 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. Methods CL-316,243, a specific β3AR agonist, was administered to the triple transgenic mouse model of AD (3xTg-AD) and non-transgenic controls from 15 to 16 months of age at a dose of 1 mg/kg/day i.p. Results Here, we show that β3AR agonist administration 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. Conclusions 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.

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 ).…”

Hypertension and hyperhomocysteinemia as modifiable risk factors for Alzheimer's disease and dementia: New evidence, potential therapeutic strategies, and biomarkers

“…133 Tau pathology was not affected by administration of the β3AR agonist but there was a 27% reduction of the insoluble Aβ42/Aβ40 ratio in the hippocampus of 3xTg-AD mice. 133 This collection of experimental results demonstrates that beta-blockers have been found to be associated with both decreased or increased AD pathology and risk. Additionally, it has been shown that agonism of beta-adrenergic receptors can also be bene-ficial on AD pathology development.…”

Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

“…Animal studies have revealed that selective activation of β 1 -AR activates the cAMP/PKA/CREB pathway to rescue social memory deficit in APP mice ( Coutellier et al, 2014 ), as well as inhibiting the expression of neuroinflammatory markers (e.g., ionized calcium binding adapter molecule 1) and reducing Aβ and tau pathology in 5 × FAD mice ( Ardestani et al, 2017 ). Moreover, treatment with CL-316243, a β 3 -AR agonist, could reduce Aβ pathology and reverse memory loss ( Gibbs et al, 2010 ; Tournissac et al, 2021 ; Table 2 ). Therefore, the current consensus is that pharmacological activation of β 1 - and β 3 -ARs is beneficial in AD.…”