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Pathological Alterations of Tau in Alzheimer's Disease and 3xTg-AD Mouse Brains.

Molecular neurobiology (2019-02-09)
Longfei Li, Yanli Jiang, Wen Hu, Yunn Chyn Tung, Chunling Dai, Dandan Chu, Cheng-Xin Gong, Khalid Iqbal, Fei Liu

Microtubule-associated protein tau in Alzheimer's disease (AD) brain is hyperphosphorylated, truncated, and aggregated into neurofibrillary tangles. Oligomeric and hyperphosphorylated tau (Oligo-tau) isolated from AD brain captures and templates normal tau into filaments both in vitro and in vivo; this prion-like activity is believed to be responsible for the progression of neurofibrillary pathology in AD. The 3xTg-AD mouse model develops both Aβ and tau pathologies and thus gains popularity in preclinical studies of AD. Despite the histopathological similarity of the 3xTg-AD model to AD, biochemical authenticity of tau alterations in this model remains elusive. To investigate the biochemical basis of tau pathology in 3xTg-AD brain, we here compared pathological alterations of tau in the aged 3xTg-AD brain to those in AD brain. We found that in contrast to substantial high molecular weight smear tau (HMW-tau) lacking the N-terminal portion and hyperphosphorylated at multiple sites in AD brain, tau in 3xTg-AD mouse brain showed no detectable HMW-tau or truncation but slightly increased phosphorylation when normalized with total tau. In addition, AT8 immunostaining exhibited filamentous tau inclusions in AD brain, but predominantly truffle-like morphology in aged 3xTg-AD mouse brain. Further, Oligo-tau isolated from 3xTg-AD mice showed minimal potency in capturing tau in vitro and seeding tau aggregation in cultured cells when compared to AD Oligo-tau. These findings suggest that the alterations of tau in 3xTg-AD mouse brain differ from those in AD brain. In 3xTg-AD mice, the lack of N-terminal truncation, scarce SDS/reducing reagent-resistant HMW-tau, and minimal hyperphosphorylation may collectively result in low potency in prion-like activity of the Oligo-tau.

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Anti-GAPDH antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution