Microtubule-associated protein tau aggregates (Tau aggregates)

Microtubule-associated protein tau (MAPT) aggregates, including soluble oligomers and insoluble neurofibrillary tangles (NFTs), are the defining pathological hallmarks of a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia (UniProt P10636) [16]. In healthy neurons, tau protein stabilizes axonal microtubules and facilitates intracellular transport; however, pathological hyperphosphorylation causes tau to detach from microtubules and self-assemble into toxic, misfolded species [8, 18]. These aggregates disrupt cellular proteostasis, impair synaptic function, and propagate through the brain via a prion-like seeding mechanism, where pathological tau is transmitted between interconnected neurons [5, 7]. Current drug development efforts focus on several modalities: monoclonal antibodies (e.g., semorinemab, bepranemab) to intercept extracellular tau seeds, small molecule aggregation inhibitors (e.g., LMTM) to prevent fibril formation, and antisense oligonucleotides (e.g., BIIB080) to lower total tau levels [6, 15]. While targeting tau is considered highly promising due to its strong correlation with cognitive decline, challenges remain regarding the optimal timing of intervention and the potential for adverse effects from reducing functional tau levels [4, 14].

Other names

Tau oligomersTau fibrilsNeurofibrillary tangles (NFTs)Paired helical filaments (PHFs)Pathological tauSoluble tau assemblies (STAs)MAPT aggregates

Therapeutic strategies include monoclonal antibodies designed to clear extracellular tau seeds and prevent cell-to-cell spread, small molecule inhibitors that prevent the aggregation of tau monomers or dissolve existing fibrils, and antisense oligonucleotides (ASOs) that reduce the overall expression of the MAPT gene to lower the pool of tau available for aggregation. Other approaches include stabilizing microtubules to compensate for loss of function and enhancing the clearance of aggregates via the autophagy-lysosome or ubiquitin-proteasome pathways [2, 6, 12].