| First Author | Wisely EV | Year | 2014 |
| Journal | Hum Mol Genet | Volume | 23 |
| Issue | 15 | Pages | 4024-34 |
| PubMed ID | 24626633 | Mgi Jnum | J:210986 |
| Mgi Id | MGI:5572998 | Doi | 10.1093/hmg/ddu116 |
| Citation | Wisely EV, et al. (2014) Genetic suppression of beta2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. Hum Mol Genet 23(15):4024-34 |
| abstractText | 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 (beta2ARs) from a mouse model overexpressing mutant human tau. Notably, the number of beta2ARs 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 beta2AR gene had a reduced mortality rate compared with the parental tau transgenic mice. Removing the gene encoding the beta2ARs 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 beta2AR-mediated changes in tau were linked to a reduction in the activity of GSK3beta and CDK5, two of the major tau kinases. These studies provide a mechanistic link between beta2ARs 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 beta2ARs could be exploited to develop better therapeutic strategies for AD and other tauopathies. |
