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Calpains are involved in calcium-induced neuronal cell toxicity, which is associated with the pathophysiology of Alzheimer's disease (AD). The activity of calpains is regulated by the inhibitor calpastatin, and increased activity of calpains and decreased calpastastin are often found in AD. Histone deacetylase (HDAC) inhibitors are implicated in AD treatment through the improvement of learning and memory but the underlying mechanism is yet to be understood. Here, using SH-SY5Y neuroblastoma cells and a calcium ionophore ionomycin, we examined whether and how HDAC inhibitor trichostatin A (TSA) inhibits calcium-induced neuronal cell death. TSA increased both the mRNA and protein levels of calpastatin, with no alterations in those of calpain 1 and calpain 2. Furthermore, TSA-stimulated increase of calpastatin was accompanied by a significant attenuation of ionomycin-induced autolysis of calpain 1, but not of calpain 2, and calpain-dependent 150 kDa αII spectrin cleavage. Under these conditions, however, caspase activity was unaltered. Moreover, ectopic expression of small interfering RNA of calpastatin reversed the inhibitory effect of TSA on ionomycin-induced calpain 1 autolysis and αII spectrin cleavage. Chromatin immunoprecipitation assay revealed the increased levels of acetylation at lysine 5 of histone H4 (H4K5-Ac), H3K9-Ac and H3K14-Ac within the calpastatin promoter region in TSA-treated cells relative to control cells. Finally, TSA significantly decreased ionomycin-induced cell toxicity. This study demonstrates that TSA attenuates calcium-induced neuronal cell death by the inhibition of calpain activity which is mediated in part by increased calpastatin expression via histone hyperacetylation within the calpastatin promoter region. Our study provides a novel mechanism for the neuroprotective effect of HDAC inhibitors on AD.

Park MH, Kwon DY, Jung JM, Han C, Jo I, Jo SA. Mini-Mental StatusExamination as predictors of mortality in the elderly.Objective: Because the number of elderly is increasing worldwide,cognitive dysfunction becomes important health care issue. This studyinvestigated the association between cognitive dysfunction andmortality in the elderly.Method: Data were analyzed from a longitudinal mortality follow-upstudy of 2712 Korean elderly aged 60 and over, examined in 2002 withcomplete data followed an average 6.03 years. Measurements includedsocio-demographic and clinical factors and Mini-Mental StateExamination (MMSE). MMSE was categorized into groups with no,mild, or moderate cognitive dysfunction, and the subscores of MMSEdomains were categorized into no dysfunction or dysfunction. The Coxproportional hazards models were conducted to examine theassociation between MMSE score and mortality, after adjusting forage, gender, education and other socio-demographic factors.Results: Death during follow-up occurred in 318 subjects. Themortality risk was significantly associated with the elderly with mildcognitive dysfunction [hazard ratio (HR) = 1.93] and with moderatecognitive dysfunction (HR = 2.66). Orientation-to-time(HR = 1.39) and Attention (HR = 1.48) domains of MMSE wereindependently associated with mortality.Conclusion: This study showed that cognitive dysfunctionindependently predicted mortality inthe elderly. Cognitive dysfunctionshould be considered part of identifying the elderly at high risk formortality.

The accumulation of beta amyloid (Aβ) has been a primary target for Alzheimer disease therapeutic strategies. Previously, we discovered an activity from Streptomyces sp. KK565 growth media that inhibits Aβ aggregation. The active component was an aminopeptidase and named Streptomyces sp. KK565 aminopeptidase (SKAP). SKAP cleaved N-terminal amino-acids of Aβ1–42 monomer, inhibited formation of fibrils and protected Aβ1–42-induced neurotoxicity. Over-expression of a human homolog of SKAP, glutamate carboxypeptidase II (hGCPII) in Aβ-oversynthesizing cells dramatically reduced the Aβ levels. These findings suggest a possible role of M28 family peptidases in preventing Aβ deposits in mammalian brain. Structured summary MINT- 7992796 : SKAP (uniprotkb: Q306T3 ) physically interacts (MI: 0915 ) with Abeta (uniprotkb: P05067 ) by protease assay (MI: 0435 ) MINT- 7992752 , MINT- 7992778 : SKAP (uniprotkb: Q306T3 ) binds (MI: 0407 ) to Abeta (uniprotkb: P05067 ) by protease assay (MI: 0435 )

To examine the function of SIRT1 in neuronal differentiation, we employed all-trans retinoic acid (ATRA)-induced differentiation of neuroblastoma cells. Nicotinamide inhibited neurite outgrowth and tyrosine hydroxylase (TH) expression. Inhibition of PARP or histone deacetylase did not inhibit TH expression, showing the effect to be SIRT1 specific. Expression of FOXO3a and its target proteins were increased during the differentiation and reduced by nicotinamide. FOXO3a deacetylation was increased by ATRA and blocked by nicotinamide. SIRT1 and FOXO3a siRNA inhibited ATRA-induced up-regulation of TH and differentiation. Taken together, these results indicate that SIRT1 is involved in ATRA-induced differentiation of neuroblastoma cells via FOXO3a.

There have been a few studies and inconsistent results regarding the coincidence of Parkinson's disease (PD) and atherosclerotic diseases, such as cerebrovascular disease. Carotid intima-media thickness (IMT) is a known marker for subclinical atherosclerosis. The aim of this study was to investigate the carotid IMT between PD patients and controls. We studied 43 patients with PD and 86 matched controls. The carotid IMT in PD patients was significantly smaller than in controls (0.796 +/- 0.179 mm vs. 0.913 +/- 0.237 mm, P < 0.05). In multivariate analysis, the carotid IMT was inversely associated with the duration of levodopa medication and the severity of PD. These results suggest that PD patients have a lower risk of atherosclerosis.

Objectives This study aimed to evaluate the diagnostic validity of the Beck Depression Inventory (BDI) in the elderly and to suggest an optimal cut-off score in order to screen major depressive disorder. Methods The BDI and an elderly health questionnaire were administered to 2729 subjects over the age of 60 chosen by stratified random sampling in a Ansan City, South Korea. The BDI and geriatric depression scale (GDS) were examined at about a two-year interval. A reliability and validity test, a factor analysis and an ROC curve analysis were performed. Results Eighty-four subject had depression and 2645 subjects were rated as normal. The BDI showed significant positive internal consistency (r = 0.88) and test–retest reliability (r = 0.60). Convergent validity with GDS was significantly positive (r = 0.59), and an exploratory factor analysis revealed four factors. We suggest a score of 16 as the optimal cut-off point for the BDI when screening for major depression. Conclusion The results of this study showed that the Korean version of the BDI is appropriate for screening for depression and 16 is the optimal cut-off score for the Korean elderly. Screening of elderly depression with BDI in the community would be valuable when comparing with younger adults and with their former BDI data which were taken when they were young. Copyright © 2006 John Wiley & Sons, Ltd.