title: Evidence of a Cardiovascular Function for Microtubule-Associated Protein Tau.
abstract: Aggregation of tau protein into intracellular deposits is a pathognomonic feature of tauopathies such as Alzheimer's disease (AD) and lowering tau is a prominent therapeutic strategy under development. However, the physiological function of tau protein is not well known, particularly in the periphery. Lowering tau protein risks disrupting its physiological role leading to unwanted effects. In this study, the presence of tau protein in cardiac tissue is confirmed and the functional role in the cardiovascular system and the consequences of its loss were explored. Isolated right and left atria and small mesenteric arteries from wild type and tau deficient (KO) mice of two age groups (13 and 23 months old) were used to assess cardiovascular phenotypes. Tau KO mice showed an increased systolic blood pressure and cardiac hypertrophy at 13 months, which was accompanied by a significantly lower right atrial rate and a subtle decrease in the maximum contractility to calcium, isoprenaline, and electrical sympathetic nerve stimulation. Aging tau KO mice to 23 months resulted in cardiac hypertrophy with significantly attenuated left atrial contractility, increased blood pressure, and sensitivity of isolated mesenteric arteries to angiotensin II contraction and isoprenaline relaxation compared to their younger counterparts. This study supports a functional role of tau in the heart and loss of this protein leads to a deterioration in cardiovascular performance which worsens with age. Taken together, these results provide insight into the peripheral function of tau protein, and give caution to the therapeutic strategy of lowering tau protein.
authors.affiliation: Department of Pharmacology and Therapeutics, Cardiovascular Therapeutics Unit, The University of Melbourne, VIC, Australia.
authors.forename: Ashenafi H
authors.initials: AH
authors.lastname: Betrie
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Ayton
authors.affiliation: The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Department of Pharmacology and Therapeutics, Cardiovascular Therapeutics Unit, The University of Melbourne, VIC, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Angus
authors.affiliation: Department of Neurology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Sichuan, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lei
authors.affiliation: Department of Pharmacology and Therapeutics, Cardiovascular Therapeutics Unit, The University of Melbourne, VIC, Australia.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Wright
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D046509:Tissue Culture Techniques; D016875:tau Proteins / Q000172:deficiency* / Q000235:genetics
chemical_list: C558298:Mapt protein, mouse; D016875:tau Proteins
keywords: Alzheimer’s disease; cardiovascular; heart; mesenteric arteries; pharmacology; tau protein