The State of Development for Therapies to Treat Tauopathies
The major neurodegenerative conditions are characterized by pathology deriving from a small number of misfolded or otherwise altered proteins. Amyloid-β misfolding and aggregation is thought to be the initiating event in Alzheimer's disease, which leads to the spread of altered forms of tau protein that cause the real damage. α-synuclein, once misfolded, spreads from cell to cell through the nervous system like a prion, encouraging other molecules of α-synuclein to also misfold in the same way. Once in the brain, α-syncuclein pathology gives rise to Parkinson's disease. In recent years, researchers have connected the spread of misfolded TDP-43 in the brain to a number of conditions such as frontotemporal dementia. All of these pathologies exist in aged brains to some degree, overlapping and driving dysfunction, and eventually that dysfunction will rise to the level of a named neurodegenerative condition, absent some other form of mortality cutting that process short.
As the past few decades of efforts to develop anti-amyloid therapies for Alzheimer's disease had demonstrated, the biochemistry of protein aggregates and their pathology is enormously complex and remains incompletely understood, even for amyloid-β, even after years of enormous funding for research and development. Amyloid-β clearance took decades to achieve, but does not produce the sizable benefits hoped for in patients, and the reasons why this is the case are yet to be established. It seems likely that the road ahead will be similarly challenging for the development of ways to target other common protein aggregates in the brain. With that in mind, today's open access paper is a tour of the state of development of therapies targeting tau protein aggregation in the aging brain; very different from past anti-amyloid therapy development at the detail level, but quite similar in many ways at the high level.
Therapeutic Targeting of Tauopathies: From Druggable Biology to Precision Intervention
Tauopathies comprise a group of neurodegenerative disorders caused by abnormal tau pathology, including Alzheimer's disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), etc. Despite the wide spectrum of tau-related diseases, therapeutic strategies directly targeting pathological tau remain relatively underdeveloped, and no broadly effective clinical treatment has yet to be established.
Most current tau-directed therapeutic approaches have been designed around the tau pathological cascade. Microtubule-associated protein tau (MAPT) mutations and other disease-associated processes can promote abnormal post-translational modifications (PTMs) of tau, with hyperphosphorylation being the most characteristic. Aberrantly modified tau loses microtubule-binding and stabilizing functions, aggregates into neurofibrillary tangles (NFTs), and ultimately contributes to neuronal dysfunction and degeneration. Based on the pathological mechanism, existing therapeutic strategies can be broadly classified into three categories: (1) reducing overall tau levels at both the RNA and protein levels, (2) regulating tau modifications, and (3) interfering with tau aggregation.
However, these approaches have not achieved satisfactory clinical outcomes, probably due to the complexity of tau pathology. Pathological tau can also spread between neurons, thereby facilitating the propagation of neurodegeneration. In addition, tau interacts with other pathogenic proteins, such as amyloid-β (Aβ) and α-synuclein (α-syn), creating mutually reinforcing pathological cycles that accelerate disease progression. Furthermore, tau exhibits remarkable isoform diversity, beyond abnormalities in protein structure and total amount, an imbalance in tau isoform ratios can itself drive disease development.
In this review, we summarize recent advances focusing on these challenges. Emerging therapeutic strategies are not only targeting more precise molecular sites, but are also placing greater emphasis on co-pathogenic proteins and the broader pathological processes involved in tauopathies. Moreover, by deepening our understanding of tau pathological mechanisms, we propose several potential therapeutic targets that may offer new directions for future drug development and therapeutic strategies for tau-related diseases.