Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-b (Ab) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Ab, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of c-secretase activity. Blockade of c-secretase activity by a c-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of c-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced c-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin a4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.

Alzheimer’s disease (AD) is characterized by neuronal loss and accumulation of amyloid β-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25-40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37°C to 39°C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39°C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF), and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx defective-1 (APH-1) and nicastrin (NCT), but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30°C) compared with those housed at standard room temperature (23°C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Alcohol abuse and its medical and social consequences are a major health problem in many areas of the world. The present study was conducted to evaluate the protective effect of methanolic fruit extract of Randia dumetorum (L.) on alcohol-induced liver damage in rats. Rats were divided into five different groups (n=6), group I served as a control, group II received ethanol (3 ml/100 g/day p.o.), group III served as standard group and received silymarin (50 mg/kg p.o.), group IV and V served as extract treatment groups and received 50 & 100 mg/kg methanolic extract of R. dumetorum. All the treatment protocols followed 30 days and after rats were sacrificed blood and liver were used for biochemical and histological studies, respectively. The activities serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), direct bilirubin (DB), total bilirubin (TB) and lipid peroxidation were statistically increased in rats exposed to alcohol while total protein and glutathione decreased compared to control rats. Treatment with R. dumetorum significantly decreased the elevated levels of ALT, AST, TG, DB, TB and lipid peroxidation compared to the group exposed to alcohol only. R. dumetorum significantly resulted in increased levels of total protein and reduced glutathione compared to the group that received alcohol only. Histology of the liver section of the animals treated with R. dumetorum improved the hepatotoxicity caused by alcohol. Hence the study concluded that R. dumetorum has potential hepatoprotective activity.