Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy

Abstract

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.

Top 100 most-cited articles on tau protein: a bibliometric analysis and evidence mapping

“…The substantial variance in citation numbers implies that studies related to tau protein have significantly contributed to advancing our understanding of neurodegenerative diseases. The heightened interest in tau protein research may be attributed to recent breakthroughs or advancements in this field ( Luciani et al, 2023 ; Zhang Z. Y. et al, 2023 ; Singh et al, 2024 ). Scientists have recently unveiled novel mechanisms or identified promising targets associated with tau pathology that could potentially revolutionize our understanding and treatment approaches for neurodegenerative diseases ( Kim et al, 2023 ; Kyalu Ngoie Zola et al, 2023 ; Langworth-Green et al, 2023 ).…”

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease

“…The lack of, or weak, associations of blood BD-tau with eGFR and other conditions supports the concept that the BD-tau assay, which uses an antibody binding to a contiguous amino acid sequence at the exon 4-5 junction of the MAPT gene, avoids blood-based tau from peripheral sources including the kidney. Indeed, the predominant form of tau in peripheral tissues tends to be of the big tau isoform 42,43 . The blood NfL assay which was not designed to separate out brain and peripheral sources of this protein showed a rather stronger association with eGFR across cohorts.…”

Re-Addressing Dementia by Network Medicine and Mechanism-Based Molecular Endotypes

“…Real-world aging individuals, with or without dementia, have mixed manifestations of neuropathological markers in their brains, such as AD markers, Lewy bodies, transactive response DNA binding protein 43 kDa (TDP-43) inclusions, and vascular pathologies, with almost 80% of these individuals presenting with at least two of such neuropathologies [14]. And in contrast with the model of brain-centricity, these "dementia specific" markers can be often found in organs outside the brain [15], as for example A␤ aggregates documented in skin, intestines [16], heart [17], and pancreas [18], with hyperphosphorylated tau also found in the last two.…”

“…This then leads to molecular disease definitions allowing precision diagnosis and tailored therapeutic intervention. A) The Human Disease Network, the diseasome, adapted from [23] and first presented in 2007 by Goh et al [17], was a landmark for the field of network medicine and disease research. It provided a novel perspective on the connections between various human diseases by their shared risk genes.…”

“…In addition, not all patients with AD dementia-like symptoms share the ROCG endotype. Therefore, this new mechanism-based diagnostic and therapeutic framework for dementia will be best tested in proof-of-concept adaptive clinical trials, where interventions align with the relevant mechanistic endotypes of those being treated [17].…”