Genetic suppression of β2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies

Abstract

Accumulation of the microtubule-binding protein tau is a key event in several neurodegenerative disorders referred to as tauopathies, which include Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Thus, understanding the molecular pathways leading to tau accumulation will have a major impact across multiple neurodegenerative disorders. To elucidate the pathways involved in tau pathology, we removed the gene encoding the beta-2 adrenergic receptors (β2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of β2ARs is increased in brains of AD patients and epidemiological studies show that the use of beta-blockers decreases the incidence of AD. The mechanisms underlying these observations, however, are not clear. We show that the tau transgenic mice lacking the β2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the β2ARs from the tau transgenic mice also significantly improved motor deficits. Neuropathologically, the improvement in lifespan and motor function was associated with a reduction in brain tau immunoreactivity and phosphorylation. Mechanistically, we provide compelling evidence that the β2AR-mediated changes in tau were linked to a reduction in the activity of GSK3β and CDK5, two of the major tau kinases. These studies provide a mechanistic link between β2ARs and tau and suggest the molecular basis linking the use of beta-blockers to a reduced incidence of AD. Furthermore, these data suggest that a detailed pharmacological modulation of β2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies.

Administration of a selective β2 adrenergic receptor antagonist exacerbates neuropathology and cognitive deficits in a mouse model of Alzheimer's disease

“…It is also plausible that the increase in tau pathology in the ICI-treated mice is due to a direct interaction between β2ARs signaling and tau. Toward this end, we recently showed that genetically reducing β2AR signaling significantly decreased tau pathology in the presence and absence of Aβ (Wang, et al, 2013; Wisely, et al, 2014). While these genetic data could appear counterintuitive with the data presented here, there are several mechanisms that could explain the variation between genetic and pharmacological data.…”

Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders

“…A has been shown to interact with  adrenergic receptors which regulate gene expression and the activity of receptors including AMPA-type glutamate receptors via the cAMP/PKA signaling cascade. 64,65 Phosphorylation of AMPA receptor GluA1 subunits by PKA has been shown to increase channel opening probability which results in augmented calcium entry into the cell, leading to neurotoxicity. 66 A study 67 has shown that the addition of Aβ to neuronal cultures causes neurotoxicity by strengthening calcium-dependent AMPA-receptor generated currents.…”

G Protein-Coupled Receptors (GPCRs) in Alzheimer’s Disease: A Focus on BACE1 Related GPCRs

“…Given that the change of expression levels of GPCRs would have an effect on the related biological processes, these observations suggested a potential role of GPCR in the pathological progression of AD, which requires further investigation (Blalock et al, 2004 ). Until now, numerous promising works have been done to connect GPCRs and AD pathology based on three hypotheses: the Cholinergic hypothesis, the Tau hypothesis and the Amyloid hypothesis (Thathiah and De Strooper, 2009 , 2011 ; Wisely et al, 2014 ).…”

“…Numerous studies have presented evidence that implicate GPCRs in the pathogenesis of Alzheimer’s disease (AD) and in multiple stages of the hydrolytic processing of amyloid protein precursor (APP), a precursor protein involved in the formation of amyloid plaques found in AD patients’ brain (Thathiah and De Strooper, 2009 , 2011 ; Wisely et al, 2014 ). Indeed accumulated data have shown that GPCRs can bind to β-secretase (β-site APP cleaving enzyme 1, BACE1) and γ-secretase which are key enzymes in the hydrolytic processing of APP (Liu et al, 2013 ; Nelson and Sheng, 2013 ; Thathiah et al, 2013 ).…”