Microtubule-associated protein tau (4-repeat tau) (4R tau)

The 4-repeat (4R) tau isoform is a specific variant of the microtubule-associated protein tau (MAPT) generated by the alternative splicing of exon 10, which results in four microtubule-binding repeat domains in the C-terminal region (UniProt P10636). In the healthy adult human brain, 4R tau exists in a balanced 1:1 ratio with the 3-repeat (3R) isoform, where it plays a vital role in stabilizing neuronal microtubules and facilitating efficient axonal transport (Goedert et al., 1989). However, an abnormal shift in this ratio or the selective aggregation of 4R tau is the defining characteristic of '4R tauopathies,' a group of neurodegenerative diseases that includes progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) (Williams & Lees, 2009). In these pathological states, 4R tau becomes hyperphosphorylated and forms insoluble neurofibrillary tangles that lead to progressive neuronal loss and cognitive or motor decline (NIH/NINDS). Therapeutic strategies targeting 4R tau are currently a major focus in biotechnology, utilizing monoclonal antibodies like Gosuranemab to clear extracellular tau seeds and antisense oligonucleotides like BIIB080 to reduce overall tau expression (Mullard, 2021; ClinicalTrials.gov). Monitoring these therapies typically involves advanced neuroimaging with tau-specific PET tracers and the measurement of phosphorylated tau species in cerebrospinal fluid or plasma.

Other names

MAPT4-repeat tauTau-4Four-repeat tauMicrotubule-associated protein tau isoform 2Tau isoform 4R

Passive immunization via monoclonal antibodies to neutralize extracellular tau seeds, antisense oligonucleotide-mediated reduction of MAPT mRNA to lower total tau protein levels, and small molecule inhibition of tau aggregation and hyperphosphorylation.