Neuroprotection and neurorescue against Aβ toxicity and PKC‐dependent release of non‐amyloidogenic soluble precursor protein by green tea polyphenol (‐)‐epigallocatechin‐3‐gallate

Abstract

Green tea extract and its main polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) possess potent neuroprotective activity in cell culture and mice model of Parkinson's disease. The central hypothesis guiding this study is that EGCG may play an important role in amyloid precursor protein (APP) secretion and protection against toxicity induced by beta-amyloid (Abeta). The present study shows that EGCG enhances (approximately 6-fold) the release of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) into the conditioned media of human SH-SY5Y neuroblastoma and rat pheochromocytoma PC12 cells. sAPPalpha release was blocked by the hydroxamic acid-based metalloprotease inhibitor Ro31-9790, which indicated mediation via alpha-secretase activity. Inhibition of protein kinase C (PKC) with the inhibitor GF109203X, or by down-regulation of PKC, blocked the EGCG-induced sAPPalpha secretion, suggesting the involvement of PKC. Indeed, EGCG induced the phosphorylation of PKC, thus identifying a novel PKC-dependent mechanism of EGCG action by activation of the non-amyloidogenic pathway. EGCG is not only able to protect, but it can rescue PC12 cells against the beta-amyloid (Abeta) toxicity in a dose-dependent manner. In addition, administration of EGCG (2 mg/kg) to mice for 7 or 14 days significantly decreased membrane-bound holoprotein APP levels, with a concomitant increase in sAPPalpha levels in the hippocampus. Consistently, EGCG markedly increased PKCalpha and PKC in the membrane and the cytosolic fractions of mice hippocampus. Thus, EGCG has protective effects against Abeta-induced neurotoxicity and regulates secretory processing of non-amyloidogenic APP via PKC pathway.

Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

“…A great deal of research has been devoted to the ability of green tea catechins, especially EGC-3-gallate, to activate the PKC pathway (171,173,174) . Notably, a 2-week pretreatment with a green tea catechin (EGC-3-gallate) was shown to be protective against Ab-induced neurotoxicity by attenuating the depletion of PKC isoforms in the hippocampus and decreasing amyloid precursor protein (173) . The PKC family has a fundamental role in the regulation of cell survival (175,176) , LTP and memory consolidation (177)(178)(179) .…”

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

“…In addition, EGCG administration increased the expression of two putative a-secretases, TACE and ADAM-10, correlating with increased levels of aCTF and sAPPa and decreased concentrations of Ab 40 and Ab 42 . This effect was abolished in the presence of the a-secretase inhibitor, Ro31-9790, or following ADAM-10 siRNA knockdown [Levites et al, 2003;Obregon et al, 2006;Rezai-Zadeh et al, 2005]. Furthermore, EGCG dose-dependently inhibits BACE1 activity in vitro [Jeon et al, 2003].…”

“…EGCG is the major polyphenolic component of green tea and has been implicated in the prevention of age-related neurodegenerative disorders such as AD. A variety of experimental in vitro cell culture paradigms have shown micromolar concentrations of EGCG to be protective against Ab-induced cell death [Bastianetto et al, 2006;Kim et al, 2007;Levites et al, 2003]. Further, i.p.…”

“…and intracerebroventricular administration of EGCG to Tg2576 mice decreases soluble and insoluble levels of Ab 40 and Ab 42 and reduces plaque load by 40-50% across the hippocampus and cortex of treated animals [Rezai-Zadeh et al, 2005]. A variety of mechanisms, including antiaggregation, anti-inflammatory, antioxidative, and iron-chelating capabilities have been proposed to mediate these neuroprotective effects [Bastianetto et al, 2006;Kim et al, 2007;Levites et al, 2003;Obregon et al, 2006;Rezai-Zadeh et al, 2005;Reznichenko et al, 2006]. For instance, EGCG treatment induced an upregulation in pro-survival mitogen activated protein kinase (MAPK) phosphatase-1 levels and antagonized Ab/IL-1-induced p38MAPK and JNK phosphorylation [Kim et al, 2007].…”

“…Treatment of human SH-SY5Y neuroblastoma and N2a swe cells with EGCG induced a dose-and time-dependent increase in the levels of sAPPa and secreted a-Cterminal fragment (CTF), without altering holo-APP expression [Levites et al, 2003;Rezai-Zadeh et al, 2005]. In addition, EGCG administration increased the expression of two putative a-secretases, TACE and ADAM-10, correlating with increased levels of aCTF and sAPPa and decreased concentrations of Ab 40 and Ab 42 .…”