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

Microtubule-associated protein tau (MAPT) amyloid fibrils are insoluble, hyperphosphorylated aggregates that serve as a primary pathological hallmark of Alzheimer's disease and various tauopathies [2, 6]. In healthy neurons, tau protein stabilizes microtubules to facilitate axonal transport; however, in disease states, tau undergoes abnormal post-translational modifications, such as hyperphosphorylation and acetylation, leading to its dissociation from microtubules and subsequent self-assembly into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) [1, 3]. These fibrils disrupt cellular homeostasis, impair synaptic function, and promote neurodegeneration, with their spatial distribution in the brain correlating closely with cognitive decline [8, 17]. Therapeutic interventions targeting these fibrils include small-molecule aggregation inhibitors like LMTX, which aim to prevent or reverse protein clumping, and monoclonal antibodies such as semorinemab and bepranemab, which target extracellular tau to block its prion-like propagation between neurons [4, 14, 15]. Despite the development of diverse strategies, including vaccines and antisense oligonucleotides, clinical success has been limited, highlighting the need for early intervention and potentially combination therapies targeting both tau and amyloid-beta [9, 18].

Other names

Neurofibrillary tangles (NFTs)Paired helical filaments (PHFs)Tau aggregatesTau inclusionsPathological tau

Inhibition of tau aggregation, disaggregation of existing fibrils, clearance of extracellular tau seeds via immunotherapy, and reduction of tau expression using antisense oligonucleotides [3, 4, 11, 16].