Microtubule-associated protein tau (Tau) (Tau)

Microtubule-associated protein tau (MAPT) is a phosphoprotein that primarily functions to stabilize microtubules within neuronal axons, supporting essential processes like intracellular transport and structural maintenance (UniProt P10636). In Alzheimer's disease and other tauopathies, tau undergoes pathological hyperphosphorylation, leading to its dissociation from microtubules and subsequent self-assembly into toxic oligomers and insoluble neurofibrillary tangles (NFTs) (NIH, 2023). These aggregates are a hallmark of neurodegeneration and their spatial distribution in the brain, described by Braak staging, correlates strongly with the severity of cognitive decline (PubMed: 31034789). Therapeutic strategies targeting this molecule focus on preventing the "seeding" and spread of tau pathology through the brain using monoclonal antibodies or small molecule inhibitors that disrupt the aggregation process (Nature Reviews Drug Discovery, 2020). Additionally, the development of tau-specific PET tracers and fluid biomarkers for phosphorylated tau epitopes has revolutionized the ability to diagnose the disease and monitor the efficacy of tau-targeted therapies in clinical trials (FDA, 2020; PubMed: 32726801).

Other names

MAPTPHF-tauNeurofibrillary tanglesHyperphosphorylated tauAggregated tauPaired helical filament-tau

Therapeutic strategies targeting aggregated tau include: 1) Passive immunization with monoclonal antibodies to neutralize extracellular tau "seeds" and prevent trans-synaptic spread (PubMed: 29377304); 2) Small molecule inhibitors designed to block the protein-protein interactions required for tau aggregation into filaments (PubMed: 30107563); 3) Antisense oligonucleotides (ASOs) that reduce the overall production of tau protein to lower the substrate available for aggregation (PubMed: 37105174); and 4) Kinase inhibitors aimed at reducing the hyperphosphorylation that triggers tau's detachment from microtubules and subsequent aggregation (PubMed: 25160684).