Abstract
Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., MAPT mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed.
Highlights
Over a century after its first described case, Alzheimer’s disease (AD) is the most prevalent form of tauopathy and the most common cause of dementia (~60–80% of cases), and its frequency of incidence is rapidly increasing as the world’s population aged >65 continues to increase
Tau misfolding and aggregation into highly ordered β-sheet-rich paired helical filaments (PHFs) that subsequently deposit in the form of neurofibrillary tangles (NFTs) (Figure 1b) are implicated in a heterogeneous group of aging-related neurodegenerative disorders referred to as tauopathies, which include Alzheimer’s disease (AD), Pick’s disease (PiD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP) (Table 1) [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]
The ubiquitin proteasome system (UPS) has been shown to be associated with disease pathogenesis with a progressive reduction in function. This means that the use of tau degraders in neurodegenerative diseases like tauopathies may rely on combined therapy approaches that signal proteins for proteasome degradation and concomitantly enhance the proteasome proteolytic function
Summary
Over a century after its first described case, Alzheimer’s disease (AD) is the most prevalent form of tauopathy and the most common cause of dementia (~60–80% of cases), and its frequency of incidence is rapidly increasing as the world’s population aged >65 continues to increase. In the human central nervous system (CNS), six tau isoforms are expressed by alternative splicing of the MAPT exons 2, 3, and 10, of which the longest isoform 2N4R tau (441 amino acids) contains two N-terminal inserts and four repeat domains in the C-terminus region (Figure 1a) [9]. This process is developmentally regulated and specific to each brain region based on physiological function [10,11]. In an effort to connect the knowledge from these two research fields, here we will review the current and ever-evolving understanding of the mechanisms of tau pathogenicity and respective approaches to therapeutics development
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