3R and 4R tau isoforms in paired helical filaments in Alzheimer’s disease

Excerpt

Isoform-specific tau antibodies RD3 and RD4 are useful tools for investigating expression and localization of three-repeat (3R) and four-repeat (4R) tau isoforms. Recently, transition from 3R to 4R tau in Alzheimer’s disease (AD) was proposed based on immunohistochemical studies with RD3 and RD4 [3]. Here, we show that two factors influence immunoreactivity to these antibodies. First, deamidation at the RD4 epitope abrogates immunoreactivity to RD4, and second, presentation of RD3 and RD4 epitopes is reciprocally affected by protease. Asparagine at position 279 in the RD4 epitope is predominantly deamidated to aspartic acid in pathological tau in AD brains [2, 4]. Consequently, the presence of 4R tau in AD pathologies may be underestimated when RD4 is used. However, anti-4R (available from Cosmo Bio Co., Ltd.) raised against RD4 peptide with N279D substitution stained both wild-type and deamidated 4R tau, and strongly stained RD3+/RD4− tangles and smearing tau fragments in Sarkosyl-insoluble fraction of AD brain [2]. …