Statistical comparisons == Statistical differences for multiple comparisons were determined by ANOVA followed by Student Newman-Keuls. calcium. Keywords:Calcium, Endoplasmic reticulum, Mitochondria, Ketoglutarate dehydrogenase == 1. INTRODUCTION == Multiple changes including abnormalities in glucose and calcium homeostasis are apparent in autopsy brains and cells from patients that died with Alzheimers Disease (AD). An understanding of the pathological order of events that lead to AD is important for understanding the disease Mcl-1-PUMA Modulator-8 process and for drug development. Although in the genetic forms of AD the cause is known, in the vast majority of cases of AD, the causative event is unknown. The experiments described in this manuscript test whether altered mitochondrial function can lead to the calcium changes that occur in cells from AD patients. == 1.1 Glucose metabolism in AD == A decline in glucose metabolism is an early and invariant change in AD that predicts who will get AD and who will progress from mild cognitive impairment to AD (Jack CR Jr et al, 2010;Mosconi et al, 2008). Reduced activities in brain homgenates of key mitochondrial tricarboxylic acid (TCA) cycle enzymes, whose decline is highly correlated to the clinical dementia rating of the patients before they died (Bubber et al, 2005), may underlie the AD-related reductions in brain metabolism. The decline in the TCA cycle -ketoglutarate dehydrogenase complex (KGDHC) may be particularly important (Gibson et al, 2005;Gibson et al, 2000;Gibson et al, 1988,Chinopoulos & Adam-Vizi, 2006;Tretter & Adam-Vizi, 2000). Reductions in KGDHC can be directly related to the pathophysiology. Reductions in KGDHC activity promote plaque Mcl-1-PUMA Modulator-8 and tangle formation which suggests that the mitochondrial changes can be an upstream event (Dumont et al, 2009;Karuppagounder et al, 2009). The focus of this paper is to determine whether a reduction in KGDHC can also lead to the abnormalities in calcium regulation that accompany AD. == 1.2. Calcium regulation in AD == Calcium regulation is known to be altered with aging and AD (Berridge, 2010;Bezprozvanny & Mattson, 2008;Gibson & Peterson, 1987;Peterson et al, 1985;Stutzmann, 2007;Supnet & Bezprozvanny, 2010). Calcium uptake is diminished in fibroblasts (Peterson et al, 1985) and lymphocytes (Gibson et al, 1987) from patients with AD. Furthermore, inositol trisphosphate (IP3) sensitive calcium stores in the endoplasmic reticulum (ER) are exaggerated in fibroblasts from AD patients (Ito et al, 1994), in fibroblasts and neurons cultured from mice bearing presenilin-1 (PS-1) mutations (Leissring et al, 2000), Mcl-1-PUMA Modulator-8 and in hippocampus and cortical neurons from 3XTg AD mice (Stutzmann et al, 2004;Stutzmann et al, 2006). Two possible mechanisms have been proposed to underlie the exaggerated ER calcium stores in cells bearing PS-1 mutations. Presenilins control the ER calcium leak channels, and PS-1 mutations that cause AD block these channels (Nelson et al, 2007;Tu Mcl-1-PUMA Modulator-8 et al, 2006). The second possibility is that mutations in presenilin interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exaggerated cellular Ca2+ signaling in response to agonist stimulation (Cheung et al, 2008,Cheung et al., 2010). ER calcium stores are also altered in fibroblasts from AD patients without presenilin mutations (i.e., the vast majority of patients). In these patients, the cause of the changes in calcium regulation is unknown. AD-causing mutations also alter cytosolic free calcium ([Ca2+]i) (Supnet & Rabbit Polyclonal to Dyskerin Bezprozvanny, 2010). PS-1 mutations enhance synaptosomal [Ca2+]ifollowing exposure to depolarizing agents, A or mitochondrial toxins (Begley et al, 1999a). Diminishing the calcium release from ER completely abrogates the enhanced mitochondrial dysfunction in synaptosomes from PS-1 mutant mice (Begley et al, 1999a). == 1.3. Linkage of mitochondria and endoplasmic reticulum.
