Microtubule-associated protein tau (4R isoforms) (MAPT (4R))

Microtubule-associated protein tau (MAPT) is a critical neuronal protein responsible for stabilizing microtubules and facilitating axonal transport [3, 12]. In the adult human brain, alternative splicing of the MAPT gene generates six major isoforms, categorized by the presence of three (3R) or four (4R) microtubule-binding repeat domains [7, 10]. The 4R tau isoforms, which incorporate exon 10, exhibit a higher affinity for microtubules and are essential for maintaining cytoskeletal stability [3, 13]. However, the pathological hyperphosphorylation and aggregation of 4R tau are defining features of several neurodegenerative diseases, collectively termed 4R tauopathies, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) [1, 2, 4]. Therapeutic interventions targeting 4R tau aim to reduce its concentration or prevent its aggregation using monoclonal antibodies, antisense oligonucleotides, and small molecule inhibitors, with the goal of slowing or halting neurodegeneration [7, 9, 17]. Monoclonal antibodies like bepranemab and gosuranemab are designed to neutralize extracellular tau seeds to prevent spread, while antisense oligonucleotides like BIIB080 target the genetic source to reduce total tau levels [11, 19]. Despite the promise of these approaches, challenges remain regarding blood-brain barrier penetration and the potential for disrupting the physiological functions of tau [7, 18].

Other names

4-repeat tau4R-tauMAPTTau-4RMicrotubule-associated protein tau isoform 2 (1N4R)Microtubule-associated protein tau isoform 7 (0N4R)Microtubule-associated protein tau isoform 8 (2N4R)

Therapeutic strategies targeting 4R tau include passive immunization with monoclonal antibodies to neutralize extracellular tau seeds [7, 11], antisense oligonucleotides (ASOs) or siRNA to reduce total tau expression or modulate exon 10 splicing to restore the 3R:4R ratio [7, 19], and small molecule inhibitors designed to prevent pathological protein aggregation [7, 9].