Ubiquitin is Associated with Early Truncation of Tau Protein at Aspartic Acid⁴²¹ during the Maturation of Neurofibrillary Tangles in Alzheimer's Disease

Abstract

Pathological processing of tau protein during the formation and maturation of neurofibrillary tangles (NFTs) includes abnormal phosphorylation, conformational changes and truncation of the C-terminus at aspartic-acid(421) (apoptotic product) and glutamic-acid(391) residues. Abnormal phosphorylation and misfolding may serve as recognition signals for ubiquitin-targeting and proteosomal processing. For this reason, we sought to determine whether ubiquitin-targeting of tau is associated with particular tau modifications that herald specific stages of NFTs maturation in the hippocampus of Alzheimer's disease cases. Using multiple tau antibodies, we found that 30% of the total load of NFTs is ubiquitin-associated. As reported previously ubiquitin immunoreactivity was associated with markers of phosphorylated tau in certain NFTs; however, a strong association was also found between ubiquitin and the earliest known truncation event at aspartic-acid(421) . These findings indicate that tau protein in the NFTs may be dually subjected to both apoptotic and proteosomal processing. By contrast ubiquitin immunoreactivity was poorly associated with truncation of tau at glutamic-acid(391) , suggesting that this proteolytic event may be independent of proteosomal activity. It would appear, therefore, that ubiquitin targeting of tau protein occurs at NFTs in the early and intermediate stages of the maturation.

Glial and Neuronal Tau Pathology in Tauopathies

“…Moreover, tau truncation in neurons at aspartic acid 421 is needed for the full cascade of NFT formation, including recruitment of fulllength tau to occur (34Y36). Finally, a strong association has been found between tau truncation at aspartic acid 421 and ubiquitin deposition in neurons in AD (45).…”

Structure and Pathology of Tau Protein in Alzheimer Disease

“…During the progression of the disease, Asp 421 -truncation is an early event that precedes the second truncation of the C-terminus at the Glu 391 , the later occurring from intermediate to advanced stages of NFTs evolution [163]. A recent report indicates that tau protein in NFTs may be dually subjected to both apoptotic and proteosomal proteolysis since strong ubiquitination was found in Asp 421 -truncated tau associated with the neurofibrillary pathology in AD [165]. …”

Proteolytic Cleavage of Polymeric Tau Protein by Caspase-3: Implications for Alzheimer Disease

“…Frozen and formalin-fixed AD brain tissue samples were obtained from the sources cited previously (15,50). Samples of brain tissue from a cohort of 17 AD cases and agematched control individuals were obtained from the Cambridge Project for Long Life collection (Table).…”

“…In some experiments, quantification of colocalization was expressed as the ratio of double labeled NFTs (positive to a tau antibody and TR) to the total number of TR-positive NFTs (50). Samples were observed through 40Â (N.A., 1.3) and 63Â (N.A., 1.4) HC Plan-Apochromat CS2 oil immersion lens to evaluate colocalization in single optical sections.…”