Accumulation of Aspartic Acid421- and Glutamic Acid391-Cleaved Tau in Neurofibrillary Tangles Correlates With Progression in Alzheimer Disease

摘要

Truncations of tau protein at aspartic acid⁴²¹ (D⁴²¹) and glutamic acid³⁹¹ (E³⁹¹) residues are associated with neurofibrillary tangles (NFTs) in the brains of Alzheimer disease (AD) patients. Using immunohistochemistry with antibodies to D⁴²¹- and E³⁹¹-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 D⁴²¹- or E³⁹¹-truncated tau correlated with clinical dementia index and Braak staging in AD. Glutamic acid³⁹¹ tau truncation was prominent in the entorhinal cortex, whereas D⁴²¹ truncation was prominent in the subiculum, suggesting that NFTs composed of either D⁴²¹- or E³⁹¹-truncated tau may be formed mutually exclusively in these areas. Both truncations were associated with the prevalence of the apolipoprotein E ε4 allele. By double labeling, intact tau in NFTs was commonly associated with D⁴²¹-cleaved tau but not with E³⁹¹-truncated tau; D⁴²¹-cleaved tau was never associated with E³⁹¹-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.