title: 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.
authors.affiliation: Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Wisely
authors.affiliation: Department of Pharmacology, University of California at Davis, Davis, CA, USA.
authors.forename: Yang K
authors.initials: YK
authors.lastname: Xiang
authors.affiliation: Department of Physiology and The Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Banner Sun Health Research Institute, Sun City, AZ, USA Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Sun City, AZ, USA oddo@email.arizona.edu.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oddo
mesh_terms: D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D016019:Survival Analysis; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018343:Receptors, Adrenergic, beta-2; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495906:Cdk5 protein, mouse; D038362:Glycogen Synthase Kinase 3