TY - JOUR
T1 - Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction
T2 - from discovery to therapy
AU - Luciani, Marco
AU - Montalbano, Mauro
AU - Troncone, Luca
AU - Bacchin, Camilla
AU - Uchida, Keita
AU - Daniele, Gianlorenzo
AU - Wolf, Bethany Jacobs
AU - Butler, Helen M.
AU - Kiel, Justin
AU - Berto, Stefano
AU - Gensemer, Cortney
AU - Moore, Kelsey
AU - Morningstar, Jordan
AU - Diteepeng, Thamonwan
AU - Albayram, Onder
AU - Abisambra, José F.
AU - Norris, Russell A.
AU - Di Salvo, Thomas G.
AU - Prosser, Benjamin
AU - Kayed, Rakez
AU - del Monte, Federica
N1 - Publisher Copyright:
© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Background Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer's disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies 'beyond the brain'. This study aims to establish tau's putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). Methods and results A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. Conclusion The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.
AB - Background Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer's disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies 'beyond the brain'. This study aims to establish tau's putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). Methods and results A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. Conclusion The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.
KW - Alzheimer's
KW - HMW tau
KW - Heart failure
KW - immunotherapy
KW - tau protein
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U2 - 10.1093/eurheartj/ehad205
DO - 10.1093/eurheartj/ehad205
M3 - Article
AN - SCOPUS:85159592862
SN - 0195-668X
VL - 44
SP - 1560
EP - 1570
JO - European Heart Journal
JF - European Heart Journal
IS - 17
ER -