Abnormally phosphorylated tau protein related to the formation of neurofibrillary tangles and neuropil threads in the cerebral cortex of sheep and goat

Aim: The aim of the present study is to investigate the effect of flavonoids from stem and leaf of Scutellaria baicalonsis Georgi (SSF) on multi-sites phosphorylation of tau protein in cerebral cortex and hippocampus of rats induced by okadaic acid (OA) and the regulative mechanism of the protein kinases. Methods: The model of AD-like memory impairment and neuronal injuries was established in male SD rats who were microinjected with OA (200 ng/kg) to establish a memory impairment model and screened for successful model rats by Morris water maze on day 21 after surgery. The successful model rats were continuously administered with intragastric infusion (ig) SSF 25, 50, and 100 mg/kg or Ginkgo biloba leaves flavonoids (GLF) 200 mg/kg for 36 d. The relative protein expressed levels of phosphorylated tau protein at sites of Ser199, Ser202, Ser214, Ser404 and Thr231, protein kinases (CDK5, PKA, pTyr216-GSK3β and pSer9-GSK3β) were detected by Western blotting. Results: The relative protein expressed levels of p-tau(Ser199), p-tau(Ser202), p-tau(Ser214), p-tau(Ser404) p-tau(Thr231), and pTyr216-GSK3β were significantly increased in both cerebral cortex and hippocampus regions of the model rats subjected to intracerebroventricular injection of OA (P<0.01), while the protein expressed levels of CDK5, PKA and pSer9- GSK3β (P<0.01) were reduced. SSF can dramatically reverse these increments in phosphorylated tau protein levels (P<0.01) and differently regulate the protein expressed levels of CDK5, PKA, and GSK3β (P<0.01) in rats’ cerebral cortex and hippocampus induced by OA. GLF also exhibits a similar effect on SSF. Conclusion: The results demonstrated that SSF could inhibit the hyperphosphorylation of tau in rats’ cerebral cortex and hippocampus induced by microinjection of OA, which may be related to the activities of protein kinase CDK5, PKA, and GSK3β.

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Autophagy and Tau Protein

International Journal of Molecular Sciences ◽

10.3390/ijms22147475 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7475

Author(s):

Tadanori Hamano ◽

Soichi Enomoto ◽

Norimichi Shirafuji ◽

Masamichi Ikawa ◽

Osamu Yamamura ◽

...

Keyword(s):

Neurofibrillary Tangles ◽

Tau Protein ◽

Therapeutic Strategy ◽

Senile Plaques ◽

Cellular Model ◽

Phosphorylated Tau ◽

Degradation Mechanisms ◽

Wild Type ◽

Lysosomal System ◽

Phosphorylated Tau Protein

Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.

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