XB-ART-56208
Cell Calcium
2018 Dec 01;76:23-35. doi: 10.1016/j.ceca.2018.09.003.
Show Gene links
Show Anatomy links
Data-driven modeling of mitochondrial dysfunction in Alzheimer's disease.
Toglia P
,
Demuro A
,
Mak DD
,
Ullah G
.
???displayArticle.abstract???
Intracellular accumulation of oligomeric forms of β amyloid (Aβ) are now believed to play a key role in the earliest phase of Alzheimer's disease (AD) as their rise correlates well with the early symptoms of the disease. Extensive evidence points to impaired neuronal Ca2+ homeostasis as a direct consequence of the intracellular Aβ oligomers. However, little is known about the downstream effects of the resulting Ca2+ rise on the many intracellular Ca2+-dependent pathways. Here we use multiscale modeling in conjunction with patch-clamp electrophysiology of single inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) and fluorescence imaging of whole-cell Ca2+ response, induced by exogenously applied intracellular Aβ42 oligomers to show that Aβ42 inflicts cytotoxicity by impairing mitochondrial function. Driven by patch-clamp experiments, we first model the kinetics of IP3R, which is then extended to build a model for the whole-cell Ca2+ signals. The whole-cell model is then fitted to fluorescence signals to quantify the overall Ca2+ release from the endoplasmic reticulum by intracellular Aβ42 oligomers through G-protein-mediated stimulation of IP3 production. The estimated IP3 concentration as a function of intracellular Aβ42 content together with the whole-cell model allows us to show that Aβ42 oligomers impair mitochondrial function through pathological Ca2+ uptake and the resulting reduced mitochondrial inner membrane potential, leading to an overall lower ATP and increased production of reactive oxygen species and H2O2. We further show that mitochondrial function can be restored by the addition of Ca2+ buffer EGTA, in accordance with the observed abrogation of Aβ42 cytotoxicity by EGTA in our live cells experiments.
???displayArticle.pubmedLink??? 30248575
???displayArticle.pmcLink??? PMC6289702
???displayArticle.link??? Cell Calcium
???displayArticle.grants??? [+]
Species referenced: Xenopus laevis
Genes referenced: itpr1
References [+] :
Alzheimer's Association Calcium Hypothesis Workgroup,
Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis.
2017, Pubmed
Alzheimer's Association Calcium Hypothesis Workgroup, Calcium Hypothesis of Alzheimer's disease and brain aging: A framework for integrating new evidence into a comprehensive theory of pathogenesis. 2017, Pubmed
Arispe, Giant multilevel cation channels formed by Alzheimer disease amyloid beta-protein [A beta P-(1-40)] in bilayer membranes. 1993, Pubmed
Baloyannis, Mitochondrial alterations in Alzheimer's disease. 2006, Pubmed
Barykin, Amyloid β Modification: A Key to the Sporadic Alzheimer's Disease? 2017, Pubmed
Berridge, Calcium hypothesis of Alzheimer's disease. 2010, Pubmed
Bezprozvanny, Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. 2008, Pubmed
Bezprozvanny, Caffeine-induced inhibition of inositol(1,4,5)-trisphosphate-gated calcium channels from cerebellum. 1994, Pubmed
Brown, The opening of the inositol 1,4,5-trisphosphate-sensitive Ca2+ channel in rat cerebellum is inhibited by caffeine. 1992, Pubmed
Bucciantini, Prefibrillar amyloid protein aggregates share common features of cytotoxicity. 2004, Pubmed
Busciglio, Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome. 2002, Pubmed
Busciglio, beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. 1995, Pubmed
Cadonic, Mechanisms of Mitochondrial Dysfunction in Alzheimer's Disease. 2016, Pubmed
Calkins, Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. 2011, Pubmed
Cao, Mapping Interpuff Interval Distribution to the Properties of Inositol Trisphosphate Receptors. 2017, Pubmed
Cao, A deterministic model predicts the properties of stochastic calcium oscillations in airway smooth muscle cells. 2014, Pubmed
Cárdenas, Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria. 2010, Pubmed
Carraro, Calcium and reactive oxygen species in regulation of the mitochondrial permeability transition and of programmed cell death in yeast. 2016, Pubmed
Chakroborty, Calcium channelopathies and Alzheimer's disease: insight into therapeutic success and failures. 2014, Pubmed
Chan, Mitochondria: dynamic organelles in disease, aging, and development. 2006, Pubmed
Cheung, Mechanism of Ca2+ disruption in Alzheimer's disease by presenilin regulation of InsP3 receptor channel gating. 2008, Pubmed
Cheung, Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. 2010, Pubmed
Clapham, Calcium signaling. 2007, Pubmed
Cortassa, An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. 2003, Pubmed
Cortassa, A mitochondrial oscillator dependent on reactive oxygen species. 2004, Pubmed
Coskun, Systemic mitochondrial dysfunction and the etiology of Alzheimer's disease and down syndrome dementia. 2010, Pubmed
Coskun, Oxidative Stress and Mitochondrial Dysfunction in Down's Syndrome: Relevance to Aging and Dementia. 2012, Pubmed
D'Andrea, Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. 2001, Pubmed
Dargan, Buffer kinetics shape the spatiotemporal patterns of IP3-evoked Ca2+ signals. 2003, Pubmed , Xenbase
Dawson, Kinetic model of the inositol trisphosphate receptor that shows both steady-state and quantal patterns of Ca2+ release from intracellular stores. 2003, Pubmed
De Caluwé, The progression towards Alzheimer's disease described as a bistable switch arising from the positive loop between amyloids and Ca(2+). 2013, Pubmed
De Felice, Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. 2007, Pubmed
Demuro, Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. 2013, Pubmed , Xenbase
Demuro, Picomolar sensitivity to inositol trisphosphate in Xenopus oocytes. 2015, Pubmed , Xenbase
Demuro, Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. 2005, Pubmed
Demuro, Calcium signaling and amyloid toxicity in Alzheimer disease. 2010, Pubmed
Demuro, Single-channel Ca(2+) imaging implicates Aβ1-42 amyloid pores in Alzheimer's disease pathology. 2011, Pubmed , Xenbase
De Young, A single-pool inositol 1,4,5-trisphosphate-receptor-based model for agonist-stimulated oscillations in Ca2+ concentration. 1992, Pubmed
Diekman, Modeling the neuroprotective role of enhanced astrocyte mitochondrial metabolism during stroke. 2013, Pubmed
Dragicevic, Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice. 2010, Pubmed
Dupont, Modeling the intracellular organization of calcium signaling. 2014, Pubmed
Fall, Mitochondrial modulation of intracellular Ca(2+) signaling. 2001, Pubmed
Ferreiro, Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. 2004, Pubmed
Foskett, Inositol trisphosphate receptor Ca2+ release channels. 2007, Pubmed
Gee, Chemical and physiological characterization of fluo-4 Ca(2+)-indicator dyes. 2000, Pubmed
Golpich, Mitochondrial Dysfunction and Biogenesis in Neurodegenerative diseases: Pathogenesis and Treatment. 2017, Pubmed
Gouras, Intraneuronal Abeta42 accumulation in human brain. 2000, Pubmed
Green, Linking calcium to Abeta and Alzheimer's disease. 2008, Pubmed
Haass, Amyloid beta-peptide is produced by cultured cells during normal metabolism. 1992, Pubmed
Hardy, Alzheimer's disease: the amyloid cascade hypothesis. 1992, Pubmed
Hartmann, Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides. 1997, Pubmed
Hashimoto, Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer's disease neuropathology. 2010, Pubmed
Hashimoto, Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. 2003, Pubmed
Helguera, Adaptive downregulation of mitochondrial function in down syndrome. 2013, Pubmed
Hertel, Inhibition of the electrostatic interaction between beta-amyloid peptide and membranes prevents beta-amyloid-induced toxicity. 1997, Pubmed
Hirai, Mitochondrial abnormalities in Alzheimer's disease. 2001, Pubmed
Hollenbeck, The axonal transport of mitochondria. 2005, Pubmed
Hu, Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. 2009, Pubmed
Iijima-Ando, Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease. 2009, Pubmed
Jensen, Alzheimer's disease-associated peptide Aβ42 mobilizes ER Ca(2+) via InsP3R-dependent and -independent mechanisms. 2013, Pubmed
Kawahara, Alzheimer's beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. 2000, Pubmed
Khachaturian, Calcium hypothesis of Alzheimer's disease and brain aging. 1994, Pubmed
Knobloch, Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. 2007, Pubmed
Knott, Mitochondrial fragmentation in neurodegeneration. 2008, Pubmed
Kornmann, An ER-mitochondria tethering complex revealed by a synthetic biology screen. 2009, Pubmed
Kowaltowski, Mitochondrial damage induced by conditions of oxidative stress. 1999, Pubmed
Kuchibhotla, Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks. 2008, Pubmed
LaFerla, Intracellular amyloid-beta in Alzheimer's disease. 2007, Pubmed
Li, Mitochondrial biogenesis in neurodegeneration. 2017, Pubmed
Lin, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. 2006, Pubmed
Lin, Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology. 2001, Pubmed
Lopez, Increased intraneuronal resting [Ca2+] in adult Alzheimer's disease mice. 2008, Pubmed
Magnus, Minimal model of beta-cell mitochondrial Ca2+ handling. 1997, Pubmed
Mak, Inositol 1,4,5-trisphosphate [correction of tris-phosphate] activation of inositol trisphosphate [correction of tris-phosphate] receptor Ca2+ channel by ligand tuning of Ca2+ inhibition. 1998, Pubmed , Xenbase
Mak, Analyzing and Quantifying the Gain-of-Function Enhancement of IP3 Receptor Gating by Familial Alzheimer's Disease-Causing Mutants in Presenilins. 2015, Pubmed
Mak, Rapid ligand-regulated gating kinetics of single inositol 1,4,5-trisphosphate receptor Ca2+ release channels. 2007, Pubmed
Mason, Distribution and fluidizing action of soluble and aggregated amyloid beta-peptide in rat synaptic plasma membranes. 1999, Pubmed
Miller, Axonal mitochondrial transport and potential are correlated. 2004, Pubmed
Mukherjee, Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. 2016, Pubmed
Murgia, Controlling metabolism and cell death: at the heart of mitochondrial calcium signalling. 2009, Pubmed
Nguyen, Effect of Ca2+ on cardiac mitochondrial energy production is modulated by Na+ and H+ dynamics. 2007, Pubmed
Nguyen, Mitochondrial calcium signaling and energy metabolism. 2005, Pubmed
Oddo, Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. 2003, Pubmed
Onyango, Regulation of neuron mitochondrial biogenesis and relevance to brain health. 2010, Pubmed
Oster, The low conductance mitochondrial permeability transition pore confers excitability and CICR wave propagation in a computational model. 2011, Pubmed
Parker, Caffeine inhibits inositol trisphosphate-mediated liberation of intracellular calcium in Xenopus oocytes. 1991, Pubmed , Xenbase
Pensalfini, Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. 2014, Pubmed
Pierrot, Intraneuronal amyloid-beta1-42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. 2004, Pubmed
Pollard, A new hypothesis for the mechanism of amyloid toxicity, based on the calcium channel activity of amyloid beta protein (A beta P) in phospholipid bilayer membranes. 1993, Pubmed
Qi, Optimal microdomain crosstalk between endoplasmic reticulum and mitochondria for Ca2+ oscillations. 2015, Pubmed
Resende, Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. 2008, Pubmed
Rizzuto, Mitochondria as sensors and regulators of calcium signalling. 2012, Pubmed
Rizzuto, Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. 1993, Pubmed
Saleet Jafri, Modeling the mechanism of metabolic oscillations in ischemic cardiac myocytes. 2006, Pubmed
Shah, TraceSpecks: A Software for Automated Idealization of Noisy Patch-Clamp and Imaging Data. 2018, Pubmed
Shuai, A kinetic model of single and clustered IP3 receptors in the absence of Ca2+ feedback. 2007, Pubmed , Xenbase
Siekmann, A kinetic model for type I and II IP3R accounting for mode changes. 2012, Pubmed
Simakova, The cell-selective neurotoxicity of the Alzheimer's Abeta peptide is determined by surface phosphatidylserine and cytosolic ATP levels. Membrane binding is required for Abeta toxicity. 2007, Pubmed
Smith, Imaging the quantal substructure of single IP3R channel activity during Ca2+ puffs in intact mammalian cells. 2009, Pubmed
Sokolov, Soluble amyloid oligomers increase bilayer conductance by altering dielectric structure. 2006, Pubmed
Supnet, Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer's disease. 2010, Pubmed
Swerdlow, A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. 2004, Pubmed
Swillens, From calcium blips to calcium puffs: theoretical analysis of the requirements for interchannel communication. 1999, Pubmed , Xenbase
Taylor, IP(3) receptors: toward understanding their activation. 2010, Pubmed
Taylor, IP(3) receptors: the search for structure. 2004, Pubmed
Texidó, Amyloid β peptide oligomers directly activate NMDA receptors. 2011, Pubmed , Xenbase
Tiwari, Oxidative stress increased respiration and generation of reactive oxygen species, resulting in ATP depletion, opening of mitochondrial permeability transition, and programmed cell death. 2002, Pubmed
Toglia, The gain-of-function enhancement of IP3-receptor channel gating by familial Alzheimer's disease-linked presenilin mutants increases the open probability of mitochondrial permeability transition pore. 2016, Pubmed
Toglia, Impaired mitochondrial function due to familial Alzheimer's disease-causing presenilins mutants via Ca(2+) disruptions. 2016, Pubmed
Tomic, Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction. 2009, Pubmed
Ullah, Mode switching of Inositol 1,4,5-trisphosphate receptor channel shapes the Spatiotemporal scales of Ca2+ signals. 2016, Pubmed
Ullah, Analyzing and Modeling the Kinetics of Amyloid Beta Pores Associated with Alzheimer's Disease Pathology. 2015, Pubmed , Xenbase
Ullah, A data-driven model of a modal gated ion channel: the inositol 1,4,5-trisphosphate receptor in insect Sf9 cells. 2012, Pubmed
Ullah, Multi-scale data-driven modeling and observation of calcium puffs. 2012, Pubmed
Ullah, Modeling the statistics of elementary calcium release events. 2006, Pubmed
Ullah, Simplification of reversible Markov chains by removal of states with low equilibrium occupancy. 2012, Pubmed
Vais, Permeant calcium ion feed-through regulation of single inositol 1,4,5-trisphosphate receptor channel gating. 2012, Pubmed
van der Bliek, Mechanisms of mitochondrial fission and fusion. 2013, Pubmed
Wacquier, Interplay Between Intracellular Ca(2+) Oscillations and Ca(2+)-stimulated Mitochondrial Metabolism. 2016, Pubmed
Wacquier, Mitochondrial Ca2+ dynamics in cells and suspensions. 2017, Pubmed
Wang, Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. 2008, Pubmed
Wang, beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. 2000, Pubmed
Wang, Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. 2014, Pubmed
Wang, Cerebellar diffuse amyloid plaques are derived from dendritic Abeta42 accumulations in Purkinje cells. 2002, Pubmed
Waters, The concentration of soluble extracellular amyloid-β protein in acute brain slices from CRND8 mice. 2010, Pubmed
Yang, On imposing detailed balance in complex reaction mechanisms. 2006, Pubmed
Yao, Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease. 2009, Pubmed
Yu, Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. 2006, Pubmed
Zampese, Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk. 2011, Pubmed
Zhang, Activity-dependent regulation of mitochondrial motility by calcium and Na/K-ATPase at nodes of Ranvier of myelinated nerves. 2010, Pubmed , Xenbase
Zhu, Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. 2013, Pubmed