Microtubule-associated protein tau (pathological aggregates) (Tau)

Microtubule-associated protein tau (MAPT) is a critical protein primarily located in neurons, where it functions to stabilize microtubules and facilitate axonal transport [10, 11]. In neurodegenerative diseases known as tauopathies, tau undergoes abnormal post-translational modifications, such as hyperphosphorylation, leading to its dissociation from microtubules and subsequent self-assembly into toxic oligomers and insoluble aggregates like neurofibrillary tangles [11, 13]. These pathological forms of tau are strongly correlated with synaptic loss, neuronal death, and cognitive decline in conditions such as Alzheimer's disease and frontotemporal dementia [4, 11]. Current drug development efforts focus on reducing tau burden through various modalities, including monoclonal antibodies that target specific tau epitopes to block the "seeding" and spread of pathology between neurons [4, 10]. Other approaches involve small molecules designed to inhibit tau aggregation or promote the clearance of existing aggregates, as well as genetic therapies like antisense oligonucleotides that lower total tau levels [4, 8, 12]. Despite numerous clinical trials, targeting pathological tau remains a significant challenge due to the complexity of its various isoforms and the difficulty of intervening effectively once neurodegeneration has progressed [4, 7].

Other names

MAPTTau proteinNeurofibrillary tanglesNFTsPaired helical filamentsPHFsTau oligomersPathological tauTau filaments

Therapeutic strategies include the use of monoclonal antibodies to neutralize extracellular tau seeds and prevent cell-to-cell spread, small molecule aggregation inhibitors to prevent the formation of toxic oligomers and fibrils, and antisense oligonucleotides (ASOs) to reduce the overall expression of the MAPT gene [4, 8, 10, 12].