RELEVANCE OF PHOSPHORYLATION AND TRUNCATION OF TAU TO THE ETIOPATHOGENESIS OF ALZHEIMER’S DISEASE

Abstract

Alzheimer's disease (AD), the major neurodegenerative disease and cause of dementia, is a slow progressive disorder pathologically characterized by extracellular amyloid-b plaques and intracellular neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau. Hyperphosphorylation and truncation of tau have been linked to the progression of the disease. However, the nature of phosphorylation and truncation of tau in AD brain is not very clear. In the present study we investigated the association of truncation with high-molecular weight oligomers of tau (HMW-tau) in post-mortem AD brain by Western blots. We found that tau from AD brain appears as a smear from low molecular weight (LMW) to HMW tau species in Western blots developed with pan-tau antibodies. Similar level of LMW-tau was found in AD and control brains, whereas HMW-tau was found in AD brain only. HMW-tau was hyperphosphorylated at multiple sites and not unphosphorylated at Ser46 or Ser198/199/202. HMW-tau was weakly labeled by tau antibodies 43D against a.a. 6-18 and HT7 against a.a. 159-163 of tau, whereas, the C-terminal antibodies, tau46 and tau46.1, strongly labeled HMW-tau. The ratio of HMW-tau/LMW-tau detected by tau antibodies increased as the epitope of tau antibodies ranges from the N- to the C-termini of tau. The level of tau truncated at Asp421 was increased in AD brain, but was poorly associated with the HMW-tau. HMW-tau is hyperphosphorylated at multiple sites, and unphosphorylated tau, such as at Ser46 and at Ser198/199/202, is absent in these aggregates. The N-terminally truncated tau is associated with HMW-tau more than the C-terminal truncated tau. These findings provide a novel insight into the association of the hyperphosphorylation and predominantly N-terminal truncation of tau with tau aggregation into oligomers in AD.