Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease

Perturbed neuronal calcium homeostasis is a prominent feature in Alzheimer's disease (AD). Mitochondria accumulate calcium ions (Ca2+) for cellular bioenergetic metabolism and suppression of mitochondrial motility within the cell. Excessive Ca2+ uptake into mitochondria often leads to mitochondrial membrane permeabilization and induction of apoptosis. Ca2+ is an interesting second messenger which can initiate both cellular life and death pathways in mitochondria. This review critically discusses the potential of manipulating mitochondrial Ca2+ concentrations as a novel therapeutic opportunity for treating AD. This review also highlights the neuroprotective role of a number of currently available agents that modulate different mitochondrial Ca2+ transport pathways. It is reasoned that these mitochondrial Ca2+ modulators are most effective in combination with agents that increase the Ca2+ buffering capacity of mitochondria. Modulation of mitochondrial Ca2+ handling is a potential pharmacological target for future development of AD treatments. © 2010 Elsevier B.V.postprin

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

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

A large-scale GWAS provides insight on diabetes-dependent genetic effects on the glomerular filtration rate, a common metric to monitor kidney health in disease.Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.</p

Interplay of the ubiquitin-proteasome system and the autophagy-lysosome pathway in cultured neurons stressed by oligomeric β-amyloid peptide

Topic: ++C.03.d. APP/Abeta: Cellular modelsHKU Seed Funding for Basic Science Research (201211159058)Program/Poster no. 40.13/G3

Green tea and neurodegeneration in Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease which remains the major health concern among the elderly, and even the middle-aged population. The pathological changes in AD start well before the cognitive dysfunction. It has been proposed that daily nutritional intervention may be a preventive measure against progression of AD. Green tea consumption has been a tradition in many Asian countries. Recent epidemiological studies demonstrate beneficial effects of green tea consumption in preventing cognitive impairment among the elderly. Most of the laboratories have focused on the anti-beta-amyloid toxicity and anti-oxidant effects of green tea. Since the pathogenesis of AD is not limited to beta-amyloid toxicity and oxidation, this article aims to review the potential protective effects of green tea of AD in a holistic way. We discuss how green tea provides direct protection to the brain, and how it modulates the risk factors for AD

Interplay of the ubiquitin-proteasome system and the autophagy-lysosomal pathway in an in vitro model of Alzheimer’s disease

Conference Theme: Aging with Confidenc

Oligomeric beta-amyloid and corticosterone trigger similar morphologic and dynamic changes in microtubules of cultured hippocampal neurons

Topic: ++C.03.d. APP/Abeta: Cellular modelsProgram/Poster no. 40.11/G31HKU Alzheimer's Disease Research Network Seed Funding for Basic Science Research 201211159058, LYCY 20000677

Corticosterone induced synaptic degeneration in depression and alzheimer's disease

Poster Presentations P09 - Depression: No. P-09-082The 27th World Congress of the Collegium Internationale Neuro-Psychopharmacologicum (CINP) 2010, Hong Kong, 6-10 June 2010

Perturbation of endoplasmic reticulum and mitochondria rather than reduced activity of mTOR trigger autophagy in neurons exposed to low molecular weight beta-Amyloid peptide

Ref. no. 247.14/H60Poster Session 247 - Alzheimer's Disease: Abeta, Energy Metabolism, Cell Signaling, AutophagyProgressive neurodegeneration is the key problem in Alzheimer’s disease (AD). Different modes of neurodegeneration including autophagy and apoptosis have been shown in AD. However, how autophagy is induced and how autophagy is transformed into apoptosis is still elusive. Our previous study has demonstrated that neurons exposed to low molecular weight β-amyloid peptide (LMW-Aβ) induce collapse of the endoplasmic reticulum (ER). Therefore, we hypothesize that disruption of intracellular organelles rather than inhibition of autophagic signaling pathway trigger the initial formation of autophagic vacuoles. Primary cultures of rat cortical neurons were prepared and transfected with LC3-, DFCP-1-, ER retention signal (KDEL)-, and mitochondrial retention signal expressing plasmids. Neurons were treated with LMW-Aβ. Protein lysates were collected afterwards for Western-blot analysis. Autophagosome, omegosome, lysosome and the morphology of the ER and mitochondria were examined by confocal microscopy. Quantitative data was analyzed by one way analysis of variance followed by Student Newman Keul test according to the statistical program SigmaStat® (Jandel Scientific) to compare the level significance. A p-value less than 0.05 was regarded as significant, at *p<0.05. We demonstrated that LMW-Aβ induced autophagic vacuoles and omegosome formation which showed partial colocalization in cortical neurons. Aβ induced AMP-activated protein kinase (AMPK) but did not cause significant suppression on mTOR and its downstream target p70S6 kinase (p70S6K) simultaneously. On the other hand, LMW-Aβ caused morphological damages in both ER and mitochondria at early time points. Organelle damage coincided with up-regulations in autophagy and lysosomal machinery. Our results suggest that LMW-Aβ first confers its toxicity on the intracellular organelles by causing structural damages to initiate autophagy. Deregulated cellular metabolism due to mitochondrial damage activates AMPK, which suppresses mTOR at later time points to exert synergistic effects on autophagy regulation.link_to_OA_fulltex

Morphological and Dynamic Changes in Microtubules of Primary Cultured Hippocampal Neurons Stressed by β-amyloid Peptide and Corticosterone

Poster Session 3Fulltext in: http://adpd.ekonnect.co/ADPD_443/poster_53336/program.aspxTopic: 03. Pathophysiology & Disease Mechanisms: 3.x. neural networksConference Theme: Mechanisms, clinical strategies, and promising treatments of neurodegenerative deiseasesObjectives: To investigate the morphological and dynamic changes in microtubules in vitro models of AD and depression. Dendrite abnormality is a common pathological feature in Alzheimer's disease (AD) and depression. Dendrites elongate with protruding synapses to form communication units between neurons. They are made up of a- and ß-tubulin subunits. Microtubule-associated proteins (MAP) like MAP2 help to stabilize its structure. One of microtubule's important characteristics is its dynamicity. A group of plus end capping proteins - for example EB3 - attaches to the plus end of the microtubule and allows the microtubule to enter and exit the synapse. This movement is important to maintain synapse morphology and plasticity. Taken together, we hypothesize that pathological alterations of microtubular dynamics could contribute to disease progression in AD and depression. Methods: Primary cultures of hippocampal neurons at 14 day were exposed to different concentrations of oligomeric ß-amyloid or corticosterone for 24/48 hours. Morphology and dynamics of microtubules in neurons were investigated with fluorescent-tagged constructs of ß-tubulin and EB3, and the use of multiphoton live-cell imaging. Results: Increased concentrations of oligomeric ß-amyloid or corticosterone led to an increase in the number and size of tubulin aggregation. Co-localization between EB3 and tubulin was decreased. Conclusions: The change in tubulin morphology and its binding with EB3 may affect the normal functioning of microtubules. This in turn may contribute to dendritic regression and synaptic abnormality in AD and depression. Our results support our hypothesis and may explain why depression promotes neurodegeneration in AD