P4‐152: Pathological Tau From Alzheimer's Brain Induces Site‐specific Hyperphosphorylation and Sds‐ and Reducing Agent‐resistant High Molecular Weight Aggregation of Tau in Vivo
Year: 2019
Type: article
Abstract: Neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau are the hallmark of Alzheimer's disease (AD) and related tauopathies. Hyperphosphorylation of tau is responsible for its loss of function, gain of toxicity and its aggregation to form NFTs. Injection of misfolded tau seeds into mouse brain induces phosphorylated tau aggregation, but the nature of tau phosphorylation in pathologic tau seeded pathology is unclear. Hyperphosphorylated and oligomeric tau isolated from AD brain (AD P-tau) was injected unilaterally into hippocampus of the human tau transgenic mice and tau knockout mice. Tau phosphorylation, the expression of tau kinases and tau phosphatases in the hippocampi and cortices were analyzed by Western blots. We found that in addition to tau pathology, AD P-tau induced hyperphosphorylation of tau at Ser202/Thr205, Thr212, Ser214, Thr217, Ser262, and Ser422 in the ipsilateral hippocampus and at Ser422 in the contralateral hippocampus and in the ipsilateral cortex. AD P-tau induced AD-like high molecular weight aggregates of tau that was SDS- and reducing agent-resistant in the injected hippocampus. There were no detectable alterations in levels of tau phosphatases or tau kinases in AD P-tau-injected brains. Furthermore, we found that hyperphosphorylated tau was easier to be captured by AD P-tau and that aggregated tau was more difficult to be dephosphorylated than non-aggregated tau by protein phosphatase 2A (PP2A). Based on these findings, we speculate that AD P-tau seeds capture hyperphosphorylated tau to form aggregation, which leads to resistance to dephosphorylation by PP2A, resulting in tau hyperphosphorylation and tau pathology.
Source: Alzheimer s & Dementia
Institution: Nantong University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980619412