Rice bran contains many phenolic acids, the most abundant of which is the antioxidant, ferulic acid (FA). We evaluated the hypoglycemic effects of a phenolic acid fraction (the ethyl acetate fraction, EAE) of rice bran and of FA in C57BL/KsJ db/db mice. Type 2 diabetic mice were allocated to a control group, an EAE group, or an FA group. Animals were fed a modified AIN-76 diet, and EAE or FA was administered orally for 17 days. There was no significant difference in body weight gain between groups. Administration of EAE and FA significantly decreased blood glucose levels and increased plasma insulin levels. EAE or FA groups had significantly elevated hepatic glycogen synthesis and glucokinase activity compared with the control group. Plasma total cholesterol and low density lipoprotein (LDL) cholesterol concentrations were significantly decreased by EAE and FA administration. These findings suggest that EAE and FA may be beneficial for treatment of type 2 diabetes because they regulate blood glucose levels by elevating glucokinase activity and production of glycogen in the liver.

Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (Abeta) in cerebral plaques. Abeta is derived from the beta-amyloid precursor protein (APP) by the enzymes alpha-, beta- and gamma-secretase. Compounds that enhance alpha-secretase, but inhibit beta- or gamma-secretase activity, have therapeutic potential in the treatment of AD. Green tea, or its major polyphenolic compound, has been shown to have neuroprotective effects. In this study, we investigated the possible effects of (-)-epigallocatechin-3-gallate (EGCG) on memory dysfunction caused by Abeta through the change of Abeta-induced secretase activities. Mice were pretreated with EGCG (1.5 or 3 mg/kg body weight in drinking water) for 3 wk before intracerebroventricular administration of 0.5 microg Abeta(1-42). EGCG dose-dependently reduced the Abeta(1-42)-induced memory dysfunction, which was evaluated using passive avoidance and water maze tests. Abeta(1-42) induced a decrease in brain alpha-secretase and increases in both brain beta- and gamma-secretase activities, which were reduced by EGCG. In the cortex and the hippocampus, expression of the metabolic products of the beta- and gamma-secretases from APP, C99, and Abeta also were dose-dependently suppressed by EGCG. Paralleled with the suppression of beta- and gamma-secretases by EGCG, we found that EGCG inhibited the activation of extracellular signal-regulated kinase and nuclear transcription factor-kappaB in the Abeta(1-42)-injected mouse brains. In addition, EGCG inhibited Abeta(1-42)-induced apoptotic neuronal cell death in the brain. To further test the ability of EGCG to affect memory, EGCG (3 mg/kg body weight) was administered in drinking water for 1 wk to genetically developed preseniline 2 (PS2) mutant AD mice. Compared with untreated mutant PS2 AD mice, treatment with EGCG enhanced memory function and brain alpha-secretase activity but reduced brain beta- and gamma-secretase activities as well as Abeta levels. Moreover, EGCG inhibited the fibrillization of Abeta in vitro with a half maximal inhibitory concentration of 7.5 mg/L. These studies suggest that EGCG may be a beneficial agent in the prevention of development or progression of AD.

Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain.Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3␤ and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.Amyloid beta peptide (A␤) generated from amyloid precursor protein (APP) is the main component of neuritic plaques in the brains of Alzheimer's disease (AD) patients, and its aggregation is hypothesized to be central to the pathogenesis of AD (28). APP, which is a type I transmembrane protein, is cleaved consecutively, first at the extracellular juxtamembrane region by ␣-or ␤-secretase and then at the intramembrane region by ␥-secretase. Following the first cleavage, a soluble APP fragment (sAPP␣ or sAPP␤) is secreted, and then, following the second cleavage, p3 or A␤ peptides and the AICD (APP intracellular domain) are generated, together with release of the cytoplasmic fragment into the cytoplasm (7,29,31,37,39).APP contains eight potential phosphorylation sites within its cytoplasmic domain (21). Seven of these potential phosphorylation sites were recently shown to be phosphorylated in AD brains, i.e., Y653, S655, T668, S675, Y682, T686, and Y687 (APP695 isoform numbering) (21). The constitutive phosphorylation of APP at T668 is observed specifically in the brain (14).

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Inflammation, insoluble protein deposition and neuronal cell loss are important features in the Alzheimer's disease (AD) brain. To investigate the regulatory genes responsible for the neuropathology in AD, we performed microarray analysis with APPV717I-CT100 transgenic mice, an animal model of AD, and isolated the S100a9 gene, which encodes an inflammation-associated calcium binding protein. In another AD animal model, Tg2576 mouse brain, and in human AD brain, induction of S100a9 was confirmed. The endogenous expression of S100a9 was induced by treatment with Aβ or CT peptides in a microglia cell line, BV2 cells. In these cells, silencing study of S100a9 showed that the induction of S100a9 increased the intracellular calcium level and up-regulated the inflammatory cytokines (IL-1β and TNFα) and iNOS. S100a9 lentiviral short hairpin RNA (sh-S100a9) was injected into the hippocampus region of the brains of 13-month-old Tg2576 mice. At two months after injection, we found that knockdown of S100a9 expression had improved the cognition decline of Tg2576 mice in the water maze task, and had reduced amyloid plaque burden. These results suggest that S100a9 induced by Aβ or CT contributes to cause inflammation, which then affects the neuropathology including amyloid plaques burden and impairs cognitive function. Thus, the inhibition of S100a9 is a possible target for AD therapy.