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

Elena V. Wisely, Yang Kevin Xiang, Salvatore Oddo

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 accumulationwill have amajor 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 amouse 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 b2AR-mediated changes in tau were linked to a reduction in the activity of GSK3b 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.

Original languageEnglish (US)
Article numberddu116
Pages (from-to)4024-4034
Number of pages11
JournalHuman Molecular Genetics
Volume23
Issue number15
DOIs
StatePublished - 2014

Fingerprint

Tauopathies
Genetic Suppression
Adrenergic Receptors
Pathology
Transgenic Mice
Neurodegenerative Diseases
Adrenergic beta-2 Receptors
Pick Disease of the Brain
Frontotemporal Lobar Degeneration
Genes
Microtubule Proteins
Progressive Supranuclear Palsy
Incidence
Brain
Epidemiologic Studies
Carrier Proteins
Alzheimer Disease
Phosphotransferases
Phosphorylation
Pharmacology

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Cite this

Genetic suppression of β2-adrenergic receptors ameliorates tau pathology in a mouse model of tauopathies. / Wisely, Elena V.; Xiang, Yang Kevin; Oddo, Salvatore.

In: Human Molecular Genetics, Vol. 23, No. 15, ddu116, 2014, p. 4024-4034.

Research output: Contribution to journalArticle

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