Aggregated paired helical filament tau (PHF-tau)

Aggregated paired helical filament tau (PHF-tau) is a pathological form of the microtubule-associated protein tau, characterized by hyperphosphorylation and misfolding into insoluble fibrils (UniProt: P10636). In its healthy state, tau stabilizes microtubules in axons, but in tauopathies like Alzheimer's disease, it dissociates and aggregates into neurofibrillary tangles, leading to neuronal dysfunction and death (PubMed: 30143504). These aggregates are considered a primary driver of cognitive decline, as their spread through the brain correlates closely with clinical symptoms (PubMed: 25404308). Therapeutic interventions targeting PHF-tau include monoclonal antibodies designed to intercept tau "seeds" during cell-to-cell transmission and small molecules intended to inhibit the aggregation process or promote the disassembly of existing filaments (PubMed: 32691234). Additionally, tau-specific PET ligands like Flortaucipir have been developed to visualize these aggregates in vivo, serving as critical biomarkers for diagnosis and monitoring disease progression (FDA: 212123). Managing this target remains challenging due to the intracellular nature of the aggregates and the need to preserve the essential biological functions of soluble tau.

Other names

Neurofibrillary tanglesTau aggregatesPaired helical filamentsHyperphosphorylated tauInsoluble tau

Therapeutic strategies include the use of monoclonal antibodies to promote clearance of extracellular tau seeds, small molecule inhibitors to prevent the aggregation of monomeric tau into filaments, and antisense oligonucleotides to reduce total tau expression (PubMed: 32691234).