Effects of corticosterone and amyloid-beta on proteins essential for synaptic function: Implications for depression and Alzheimer's disease.

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Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: Implication in Alzheimer's disease pathogenesis

Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. © 2012 - IOS Press and the authors. All rights reserved.postprin

Fuzzy Modeling with Genetic Algorithms

Recent applications of fuzzy control have created an urgent demand for fuzzy modelling techniques. Several methods for identification of fuzzy models from numerical input-output samples have been proposed. Among them, Sugeno and Yasukawa's method [6], which employs fuzzy c/means clustering, holds significant promises. This paper improves the method of Sugeno and Yasukawa. Identified fuzzy models are tuned at various stages by means of genetic algorithms, i.e., the numbers of input variables and rules are reduced and membership function parameters are adjusted. The technique, when applied to a nonlinear system, demonstrates its efficiency in a comparison with the original method of Sugeno and Yasukawa

The putative neurodegenerative links between depression and Alzheimer's disease

Alzheimer's disease (AD) is the leading neurodegenerative cause of dementia in the elderly. Thus far, there is no curative treatment for this devastating condition, thereby creating significant social and medical burdens. AD is characterized by progressive cognitive decline along with various neuropsychiatric symptoms, including depression and psychosis.Depression is a common psychiatric disorder affecting individuals across the life span. Although the " monoamine hypothesis" of depression has long been proposed, the pathologies and mechanisms for depressive disorders remain only partially understood. Pharmacotherapies targeting the monoaminergic pathways have been the mainstay in treating depression. Additional therapeutic approaches focusing other pathological mechanisms of depression are currently being explored.Interestingly, a number of proposed mechanisms for depression appear to be similar to those implicated in neurodegenerative diseases, including AD. For example, diminishing neurotrophic factors and neuroinflammation observed in depression are found to be associated with the development of AD. This article first provides a concise review of AD and depression, then discusses the putative links between the two neuropsychiatric conditions. © 2010 Elsevier Ltd.link_to_subscribed_fulltex

The potential effects of antidepressants in attenuating synaptic degeneration in depression and Alzheimer's disease

Depression is a highly prevalent psychiatric disorder. Furthermore, it is one of the most common neuropsychiatric presentations in Alzheimer's disease (AD). Common underlying neuropathological processes appear to exist between these conditions. Synaptic degeneration has been implicated in AD pathogenesis, while its role in depression is not well understood. Objectives: This study aims to investigate synaptic degeneration as a possible underlying mechanism for depression and whether antidepressants could alleviate the stated pathology. Methods: Primary rodent hippocampal neurons treated with corticosterone were used as an in vitro model of depression. Toxicity of corticosterone was determined through the lactate dehydrogenase and caspase-3 activity assays. Immunocytochemical analysis of synaptic proteins was employed to investigate effects of corticosterone on synapses. Results: Neurotoxicity was observed in hippocampal neurons after treatment with corticosterone (10μM) for 24 hours. Aggregations of synaptotagmin and synaptophysin were observed 24 hours after treatment with corticosterone (10μM). Similar effects were observed after sub-lethal treatments with corticosterone (0.5μM and 1μM) for 48 and 72 hours. Pre-treatment for 1 hour with imipramine and escitalopram (20μM and 40μM for both agents) were able to alleviate these toxic effects. Conclusions: These results suggest the involvement of synaptic degeneration in corticosterone-induced toxicity and that commonly used antidepressants are able to alleviate synaptic derangements. Taken together, synaptic degeneration could be a common pathway for neuronal demise occurring in AD and depression, which can be attenuated by antidepressant administration. Future research to elucidate the precise mechanism for the synaptic protective effect of antidepressants is warranted

Exploriing the connection between depression and dementia

Poster Presentations: Theme 1 - Healthy Aging: No. 1.26The 14th Research Postgraduate Symposium, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, 2-3 December 2009

Investigation of synaptic degeneration in depression and alzheimer's disease

Conference Theme: Is Aging a Diseace