Neuroprotective Effect Of Green Tea Polyphenols On Alzheimer’s Disease Model

Alzheimer’s disease (AD) is one of the most prevalent age-dependent neurodegenerative disorders. It is characterized by mild cognitive impairment at its onset followed by irreversible neuronal degeneration and dementia later. In2001, more than24million people had dementia. The number is expected to double every20years up to81million in2040because of the anticipated increase in life expectancy. AD is characterized by presence of two aberrant structures in the patients’brains, senile plaques and neurofibrillary tangles. Senile plaques are composed of beta amyloid peptide, a fragment of the amyloid peptide precursor, whereas the main component of neurofibrillary tangles is the cytoskeleton protein known as the tau protein, in hyperphosphorylated form. Several pathogenic mechanisms that underlie these changes have been studied, including A13aggregation and deposition with plaque development, tau hyperphosphorylation with tangle formation, neurovascular dysfunction, and other mechanisms such as cell-cycle abnormalities, inflammatory processes, oxidative stress, and mitochondrial dysfunction.Recently, there is growing interest in the potential beneficial effects of green tea polyphenols (GTP) on aging and aged brain. Green tea catechins, are especially concentrated in green tea. It accounts for30-40%of the dry weight of the leaves. The major polyphenolic components in GTP are epigallocatechin-3-gallate (EGCG), epicatechin (EC),(-)-epigallocatechin (EGC) and (-)-epicatechin-gallate(ECG). Among these components, EGCG is the abundant and most active component.There is abundant of evidence, which is mostly from the preclinical and epidemiological studies, suggesting that green tea consumption is associated with a reduced risk of severe human malignancies such as cancer, cardiovascular diseases, and diabetes. More recently, either the green tea extract or its isolated catechin constituents have been reported to display neuroprotective/neurorestorative properties. A lot of studies have demonstrated that GTP exhibit multifunctional neuroprotective-neurorescue activities in cell cultures and animal models, such as antioxidant actions, free radical scavenging and iron-chelating properties. Another noteworthy feature of GTP is that they possess anti-amyloidogenic effects, protecting neuron from A_-induced neurotoxicity and regulating APP processing in vitro and in vivo. GTP may be a novel neuroprotective strategy for AD.SAM(The senescence-accelerated mouse), is a well established animal model foraging. It is a group of related inbredstrains including nine strains of accelerated-prone, short-lived mice (SAMP), and three strains of accelerated senescence-resistant, long-lived mice (SAMR). Senescence-accelerated mouse prone-8(SAMP8), a substrain of SAMP, shows early onset of learning and memory deficits. What’s more, senescence-accelerated mouse (SAMP8), which could act as a model of aging, displays many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD. And in addition, it was reported that hyperphosphorylation in some forms of tau, protein kinase GSK-3β and Cdk5activation, and increase in overall oxidative stress status in primary neurons and astrocytes of SAMP8. Therefore, we investigate the protective mechanisms of EGCG on SAMP8primary hippocampus neurons, which would be cultured for at least13days. MTT method, immunohistochemistry,RT-PCR, Western Blot were employed in this experiment. And it is revealed that, after incubated with EGCG, the growth appearance of primary neurons was improved. And EGCG could inhibit the activation of GSK-3βkinase via the PI3K/Akt pathway, subsequently resulting in less tau phosphorylation. Besides, EGCG could also decrease the activity of Cdk5through reducing p25/p35ratio which suppressed tau phosphorylation. EGCG could up-regulates the Bcl-2mRNA and protein expression, which would inhibit the cell apoptosis.Taken SAMP8mice as the AD animal model, we investigated the neuroprotective effect of GTP, with such method as Morris water maze(MWM), immunohistochemical staining, RT-PCR and western blot. Results show with long-term oral administration of GTP, that the spatial learning and memory of SAMP8in MWM were improved significantly. Immunohistochemical straining shows that the Aβ1-42positive cells in both cortex and hippocampus were reduced. It is also proved that NFTs observed with Bielschowsky method decreased after GTP treatment. And, long term GTP administration reduced the Aβ1-42level in cortex and hippocampus, inhibited the GSK-3Bactivity via PI3K/Akt pathway, decreased the Cdk5activity by modulating p25/p35ratio, subsequently reduced the tau phosphorylation. Bcl-2level was up-regulated after the GTP treatment. These results suggest that long-term GTP administration down-regulated Aβ1-42protein levels and tau phosphorylation with probable multiple pathways including PI3K/Akt pathway.The experimental results of present study support the neuroprotection of GTP and provide a new strategy of preventing and curing Alzheimer’s Disease.