الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Tauopathy is a pathological hallmark of many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD) and atypical parkinsonism e.g. PSP. They are characterized by abnormal aggregates of pathological phospho-tau and somatodendritic redistribution. One suggested strategy for treating tauopathy is to stimulate autophagy, hence, getting rid of these pathological protein aggregates. One key controller of autophagy is mTOR. Since stimulation of mTOR leads to inhibition of autophagy, inhibitors of mTOR will cause stimulation of autophagy process. Part1 In this report, tauopathy was induced in twenty four mice using annonacin. Mice are divided into three groups: Negative control(I):Negative control group (n=8) that consume water through all period of study(1year ) and then injected intracerebrally with DEPC water. • group (II): Positive control (tauopathic group n=8 )that consume graviola juice for one year. • group (III) Treated group (n=8):That consume graviola juice for one year and then treated intracerebrally by SiRNA. Two weeks after injection ,mice are euthanized. The animal model of tauopathy was assessed by : •Behavioural test: mice were assessed each 3 months by using open field test. • Quantitative PCR (qPCR) • Immunohistochemical tests: brain tissues were stained using primary antibodies (AT8 antibody against ps202/pT205 tau, mouse AT180 monoclonal phopho –PHF –tau pThr231 antibody and AD2 antibody against ps396/ps404,anti NeuN for neurons and anti-ionized calcium. Results obtained revealed that, The behavioral and immunohistochemical evaluation revealed the development of tauopathy model as proven by deterioration of behavioral performance in open field test and significant tau aggregates in annonacin-treated mice. Blocking of mTOR (treated group) revealed significant clearance of tau aggregates in the injected side; however, tau expression was not affected by mTOR blockage. Part2 In this report, tauopathy was inducedin LUHMES as recommended by the manufacturer : Purchasing of LUHMES and then culturing on different culturingmedium containing N2&tetracyclie and others .Incubationof cells at 37 °C and humid atmosphere of 5% CO2.the cells were differentiated for 4days. on day 5th we add fenezaquin to cells to enhance tauopathy .In cells needed to be treated with pp242 we added mTORC1&mTORC2 dual blockers in addition to fenezaquin. Immunostaining:cells were stained with the specified primary antibodies at 4 °C overnight anti-TH antibody purified anti-Tau phospho (Thr181) antibodyfollowed by Power-Stain that was used for qualitative detection of primary antibodies. Result obtained revealed that ; 1-shows the successful differentiation of LUHMES cells to dopaminergic neurons as evidenced by positive staining for Tyrosine hydroxylase antibodies. 2-Treatment of cells with the mitochondrial complex I inhibitor (fenazaquin) at a dose of 64nMis a significant increase in phosphorylated Tau aggregates. 3-Somato-dentritic redistribution of tau is diagnostic endpoint for tauopathy. 4-Fenazaquin treated cells showed 37% of neurons with Tau positive somata. On the other side, cells treated with fenazaquin + mTOR blockage showed significant decrease in tau aggregates. Interestingly, adding mTOR blockers caused retraction of somato-dentritic distribution of tau into the normal axonal pattern.