Accumulation of aspartic Acid421- and glutamic Acid391-Cleaved tau in neurofibrillary tangles correlates with progression in Alzheimer disease

Truncations of tau protein at aspartic acid(421) (D-421) and glutamic acid(391) (E-391) residues are associated with neurofibrillary tangles (NFTs) in the brains of Alzheimer disease (AD) patients. Using inarnumohistochemistry with antibodies to D-421- and E-391-truncated tau (Tau-C3 and MN423, respectively), we correlated the presence of NFTs composed of these truncated tau proteins with clinical and neuropathologic parameters in 17 AD and 23 non-AD control brains. The densities of NFTs composed of D-421- or E-391-truncated tau correlated with clinical dementia index and Braak staging in AD. Glutamic acid(391) tau truncation was prominent in the entorhinal cortex, whereas D-421 truncation was prominent in the subiculum, suggesting that NFTs composed of either D-421- or E-391-truncated tau may be formed mutually exclusively in these areas. Both truncations were associated with the prevalence of the apolipoprotein E epsilon 4 allele. By double labeling, intact tau in NFTs was commonly associated with D-421-deaved tau but not with E-391-truncated tau; D-421-cleaved tau was never associated with E-391-truncated tau. These results indicate that tau is not randomly proteolyzed at different domains, and that proteolysis occurs sequentially from the C-terminus to inner regions of tau in AD progression. Identification of NFTs composed of tau at different stages of truncation may facilitate assessment of neurofibrillary pathology in AD.