Microtubule-associated protein tau (MAPT) fibrils (Tau fibrils)

Pathological tau fibrils are insoluble, filamentous aggregates composed of hyperphosphorylated microtubule-associated protein tau (MAPT). In healthy neurons, tau plays a critical role in stabilizing microtubules and facilitating axonal transport (UniProt P10636). However, in neurodegenerative diseases known as tauopathies, tau undergoes post-translational modifications that cause it to detach from microtubules and self-assemble into toxic structures. These structures, including paired helical filaments (PHF) and neurofibrillary tangles (NFTs), are strongly associated with synaptic loss, neuronal death, and the progression of cognitive impairment in Alzheimer's disease (PubMed: 32165671). The aggregation process is thought to involve a prion-like mechanism where pathological tau seeds induce the misfolding of healthy tau in neighboring cells. Current therapeutic approaches primarily involve immunotherapy using monoclonal antibodies to clear extracellular tau or prevent its spread between cells (ClinicalTrials.gov). Additionally, small molecules are being investigated to inhibit the aggregation process or stabilize the native, functional state of the tau protein. Targeting tau fibrils is considered a promising strategy to slow or halt the progression of neurodegeneration in Alzheimer's and related disorders.

Other names

Paired helical filaments (PHF)Straight filaments (SF)Neurofibrillary tangles (NFTs)Tau aggregatesPathological tauPHF-tau

The primary mechanisms of action for drugs targeting pathological tau fibrils include the use of monoclonal antibodies to sequester extracellular tau and prevent its prion-like spread between neurons, small molecule inhibitors designed to prevent the aggregation of tau monomers into toxic oligomers and fibrils, and agents that promote the clearance of existing aggregates via the autophagic or proteasomal pathways (PubMed: 32165671, 30107520).