Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease

Bezprozvanny, Ilya; Mattson, Mark P.

doi:10.1016/j.tins.2008.06.005

Cited by 938Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease

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Bezprozvanny, Ilya, Mattson, Mark P.·2008·Trends in Neurosciences

DOI 10.1016/j.tins.2008.06.005PMC PMC2566585

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Abstract

Perturbed neuronal Ca(2+) homeostasis is implicated in age-related cognitive impairment and Alzheimer's disease (AD). With advancing age, neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subcellular Ca(2+) dynamics. Toxic forms of amyloid beta-peptide (Abeta) can induce Ca(2+) influx into neurons by inducing membrane-associated oxidative stress or by forming an oligomeric pore in the membrane, thereby rendering neurons vulnerable to excitotoxicity and apoptosis. AD-causing mutations in the beta-amyloid precursor protein and presenilins can compromise these normal proteins in the plasma membrane and endoplasmic reticulum, respectively. Emerging knowledge of the actions of Ca(2+) upstream and downstream of Abeta provides opportunities to develop novel preventative and therapeutic interventions for AD.

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Glucose metabolism is significantly impaired in Alzheimer disease and amnestic mild cognitive impairment brains.
“Yet glucose metabolism in AD and aMCI brains is significantly impaired5–7,9,38.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [38]
The section ‘Amyloid β-Peptide Promotes Ca2+ Influx and Ca2+-Mediated Excitotoxicity’ says Aβ-related damage impairs neuronal glucose transporters, supporting a connection between AD pathology and impaired glucose handling. The paper does not report significantly impaired brain glucose metabolism in both AD and amnestic mild cognitive impairment; its ‘Synapses: the Weakest Link’ section discusses MCI in relation to synaptic dysfunction instead. Page numbers are unavailable in our copy. (LLM, conf=0.84)
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Aβ may increase cytosolic calcium levels and impair mitochondrial calcium buffering functions through plasma membrane receptors and calcium channels, enhanced ER calcium release, and the mitochondrial inner membrane calcium channel MCU, leading to mitochondrial calcium overload, CypD relocation, mPTP formation, inhibition of ATP synthesis, and activation of oxidative stress and apoptosis.
“Aβ may increase cytosolic calcium levels and impair mitochondrial calcium buffering functions through various pathways including plasma membrane receptors and calcium channels,291 enhanced ER calcium release,292 and the mitochondrial inner membrane calcium channel MCU.293,294 This leads to mitochondrial calcium overload, causing cyclophilin D (CypD) to relocate from the mitochondrial matrix to the”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [291]
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Glucose metabolism is markedly reduced in Alzheimer disease and amnestic mild cognitive impairment.
“in AD and amnestic mild cognitive impairment (aMCI) glucose metabolism is dramatically decreased”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [38]
The section ‘Amyloid β-Peptide Promotes Ca2+ Influx and Ca2+-Mediated Excitotoxicity’ describes impaired glucose transporters, while ‘Synapses: the Weakest Link’ discusses patients with mild cognitive impairment and AD. Neither reports that glucose metabolism is markedly reduced in AD and amnestic mild cognitive impairment; searches for those terms found no such passage. Page numbers were unavailable in our copy. (LLM, conf=0.72)
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Mitochondrial dysfunction and insulin resistance are closely related.
“Indeed, mitochondrial dysfunction and insulin resistance are intimately related7,38.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [38]
The “Calcium Stability in the Face of Adversity” box discusses impaired mitochondrial calcium handling in Alzheimer’s disease, but does not connect it to insulin resistance. Searches of our full-text copy for “insulin resistance” and “insulin” found no passage addressing that relationship; page numbers were not available. (LLM, conf=0.73)
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Brain insulin resistance is common in Alzheimer disease.
“Brain insulin resistance is common in AD7,38,41.”
From Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease (2019) · cites this paper as [38]
The Abstract and the section on neuronal Ca2+ signaling discuss calcium dysregulation and impaired energy metabolism in Alzheimer’s disease, not brain insulin resistance. Searches for “brain insulin resistance,” “insulin signaling,” and “insulin” found no passage stating that insulin resistance is common in AD. (LLM, conf=0.76)
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McKee, A. C., Kosik, K. S., Kennedy, M. B., & Kowall, N. W. (1990) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199001000-00006 · Cited by 116 · see citing works
Alzheimer's disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling
Emilsson, L., Saetre, P., & JAZIN, E. E. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.09.004 · Cited by 116 · see citing works
Presenilin 2 Interacts with Sorcin, a Modulator of the Ryanodine Receptor
Pack-Chung, E., Meyers, M. B., Pettingell, W. P., Moir, R. D., Brownawell, A. M., Cheng, I., Tanzi, R. E., & Kim, T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m909882199 · Cited by 110 · see citing works
Subfield- and layer-specific changes in parvalbumin, calretinin and calbindin-D28k immunoreactivity in the entorhinal cortex in Alzheimer's disease
Mikkonen, M., Alafuzoff, I. I., Tapiola, T., Soininen, H. S., & Miettinen, R. A. (1999) · Neuroscience · doi:10.1016/s0306-4522(99)00047-0 · Cited by 110 · see citing works
The Cell-Selective Neurotoxicity of the Alzheimer's Aβ Peptide Is Determined by Surface Phosphatidylserine and Cytosolic ATP Levels. Membrane Binding Is Required for Aβ Toxicity
Šimáková, O., & Arispe, N. J. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.3006-07.2007 · Cited by 106 · see citing works
Apolipoprotein E and Alzheimer disease
Huang, Y. (2006) · Neurology · doi:10.1212/01.wnl.0000192102.41141.9e · Cited by 106 · see citing works
Comparative Study of Action Mechanisms of Dimebon and Memantine on AMPA- and NMDA-Subtypes Glutamate Receptors in Rat Cerebral Neurons
Григорьев, В. В., Dranyi, O. A., & Бачурин, С. О. (2003) · Bulletin of Experimental Biology and Medicine · doi:10.1023/b:bebm.0000017097.75818.14 · Cited by 95 · see citing works
Loss of calbindin‐D28k from aging human cholinergic basal forebrain: Relation to neuronal loss
Geula, C., Bu, J., Nagykery, N. G., Scinto, L. F. M., Chan, J. A.-W., Joseph, J. T., Parker, R. A., & Wu, C. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10475 · Cited by 95 · see citing works
Apolipoprotein E and Cholesterol Affect Neuronal Calcium Signaling: The Possible Relationship to β-Amyloid Neurotoxicity
Hartmann, H., Eckert, A., & Müller, W. E. G. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.1576 · Cited by 95 · see citing works
Annexin 5 and apolipoprotein E2 protect against Alzheimer’s amyloid-β-peptide cytotoxicity by competitive inhibition at a common phosphatidylserine interaction site
Lee, G., Pollard, H. B., & Arispe, N. J. (2002) · Peptides · doi:10.1016/s0196-9781(02)00060-8 · Cited by 93 · see citing works
Calcium buffering systems and calcium signaling in aged rat basal forebrain neurons
Murchison, D. A., & Griffith, W. H. (2007) · Aging Cell · doi:10.1111/j.1474-9726.2007.00293.x · Cited by 84 · see citing works
Non‐fibrillar β‐amyloid abates spike‐timing‐dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors
Shemer, I., Holmgren, C. D., Min, R., Fülöp, L., Zilberter, M. Y., Sousa, K. M., Farkas, T., Härtig, W., Penke, B., Burnashev, N., et al. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.04733.x · Cited by 82 · see citing works
Brain Region-Specific, Age-Related, Alterations in Mitochondrial Responses to Elevated Calcium
Brown, M. R., Geddes, J. W., & Sullivan, P. G. (2004) · Journal of Bioenergetics and Biomembranes · doi:10.1023/b:jobb.0000041775.10388.23 · Cited by 82 · see citing works
Pore-Forming Proteins Share Structural and Functional Homology with Amyloid Oligomers
Yoshiike, Y., Kayed, R., Milton, S. C. F., Takashima, A., & Glabe, C. G. (2007) · NeuroMolecular Medicine · doi:10.1007/s12017-007-0003-6 · Cited by 76 · see citing works
Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation
Furukawa, K., Wang, Y., Yao, P. J., Fu, W., Mattson, M. P., Itoyama, Y., Onodera, H., D’Souza, I., Poorkaj, P., Bird, T. D., et al. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02020.x · Cited by 70 · see citing works
Self-citation
Beta-amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress
Celsi, F., Svedberg, M. M., Lithner, C. U., Cotman, C. W., Carrı̀, M. T., Ottersen, O. P., Nordberg, A. K., & Torp, R. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.022 · Cited by 57 · see citing works
The Presenilin 1 ΔE9 Mutation Gives Enhanced Basal Phospholipase C Activity and a Resultant Increase in Intracellular Calcium Concentrations
Cedazo-Mı́nguez, Á., Popescu, B. O., Ankarcrona, M., Nishimura, T., & Cowburn, R. F. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112117200 · Cited by 51 · see citing works
Biological effects of four PSEN1 gene mutations causing Alzheimer disease with spastic paraparesis and cotton wool plaques
Dumanchin‐Njock, C., Tournier, I., Martin, C., Didic, M., Belliard, S., Carlander, B., Rouhart, F., Duyckaerts, C. J., Pellissier, J., Latouche, J., et al. (2006) · Human Mutation · doi:10.1002/humu.9458 · Cited by 49 · see citing works
Inhibitors and Modulators of β- and γ-Secretase
Schmidt, B., Baumann, S., Braun, H., et al. (2006) · Current Topics in Medicinal Chemistry · doi:10.2174/156802606776287027 · Cited by 48 · see citing works
The Presenilin-2 Loop Peptide Perturbs Intracellular Ca2+ Homeostasis and Accelerates Apoptosis
Cai, C., Lin, P., Cheung, K., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512026200 · Cited by 45 · see citing works
Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism
Petryniak, M. A., Wurtman, R. J., & Slack, B. E. (1996) · Biochemical Journal · doi:10.1042/bj3200957 · Cited by 45 · see citing works
What transgenic mice tell us about neurodegenerative disease
Gurney, M. E. (2000) · BioEssays · doi:10.1002/(sici)1521-1878(200003)22:3 · Cited by 38 · see citing works
Mutant Presenilin 1 Alters Synaptic Transmission in Cultured Hippocampal Neurons
Priller, C., Dewachter, I., Vassallo, N., Paluch, S., Pace, C., Kretzschmar, H. A., LEUVEN, F. V., & Herms, J. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605066200 · Cited by 37 · see citing works
Relationship of calbindin D28K‐immunoreactive cells and neuropathological changes in the hippocampal formation of Alzheimer's disease
Iritani, S., Niizato, K., & Emson, P. C. (2001) · Neuropathology · doi:10.1046/j.1440-1789.2001.00393.x · Cited by 34 · see citing works
Cyclical mitochondrial ΔΨM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca+2 exchange are reduced in Alzheimer's disease cybrids
Thiffault, C., & Bennett, J. P. (2005) · Mitochondrion · doi:10.1016/j.mito.2004.12.002 · Cited by 33 · see citing works

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Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging
Jomova, K., Raptova, R., Alomar, S. Y., Alwasel, S. H., Nepovimova, E., Kuca, K., & Valko, M. (2023) · Archives of Toxicology · doi:10.1007/s00204-023-03562-9 · Cited by 2,638 · see citing works
Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease
Butterfield, D. A., & Halliwell, B. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0132-6 · Cited by 1,954 · see citing works
Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease
Tönnies, E., & Trushina, E. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-161088 · Cited by 1,750 · see citing works
Calcium and ROS: A mutual interplay
Görlach, A., Bertram, K., Hudecova, S., & Krizanova, O. (2015) · Redox Biology · doi:10.1016/j.redox.2015.08.010 · Cited by 1,546 · see citing works
Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States
Mattson, M. P., & Arumugam, T. V. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.011 · Cited by 1,242 · see citing works
Self-citation
Synergy between amyloid-β and tau in Alzheimer’s disease
Busche, M. A., & Hyman, B. T. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0687-6 · Cited by 1,242 · see citing works
Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
“290 A β may increase cytosolic calcium levels and impair mitochondrial calcium buffering functions through various pathways including plasma membrane receptors and calcium channels, 291 enhanced ER calcium release, 292 and the mitochondrial inner membrane calcium channel MCU.”
Background
Mitochondria in neuroplasticity and neurological disorders
Mattson, M. P., Gleichmann, M., & Cheng, A. (2008) · Neuron · doi:10.1016/j.neuron.2008.10.010 · Cited by 1,081 · see citing works
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Mitophagy and Alzheimer’s Disease: Cellular and Molecular Mechanisms
Kerr, J. S., Adriaanse, B. A., Greig, N. H., Mattson, M. P., Cader, M. Z., Bohr, V. A., & Fang, E. F. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.01.002 · Cited by 870 · see citing works
Self-citation
NAD+ in Brain Aging and Neurodegenerative Disorders
Lautrup, S., Sinclair, D. A., Mattson, M. P., & Fang, E. F. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.001 · Cited by 790 · see citing works
Self-citation
The case for rejecting the amyloid cascade hypothesis
Herrup, K. (2015) · Nature Neuroscience · doi:10.1038/nn.4017 · Cited by 768 · see citing works
History and progress of hypotheses and clinical trials for Alzheimer’s disease
Liu, P.-P., Xie, Y., Meng, X.-Y., & Kang, J.-S. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0063-8 · Cited by 723 · see citing works
Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease
Busche, M. A., Chen, X., Henning, H. A., Reichwald, J., Staufenbiel, M., Sakmann, B., & Konnerth, A. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206171109 · Cited by 715 · see citing works
Upregulated function of mitochondria‐associated ER membranes in Alzheimer disease
Area‐Gomez, E., del Carmen Lara Castillo, M., Tambini, M. D., Guardia‐Laguarta, C., de Groof, A. J. C., Madra, M., Ikenouchi, J., Umeda, M., Bird, T. D., Sturley, S. L., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.202 · Cited by 638 · see citing works
Deleterious Effects of Amyloid β Oligomers Acting as an Extracellular Scaffold for mGluR5
Renner, M., Lacor, P. N., Velasco, P. T., Xu, J., Contractor, A., Klein, W. L., & Triller, A. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.029 · Cited by 468 · see citing works
Synapses and Alzheimer's Disease
Sheng, M., Sabatini, B. L., & Sudhof, T. C. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005777 · Cited by 436 · see citing works
Endoplasmic reticulum dysfunction in neurological disease
Roussel, B. D., Kruppa, A. J., Miranda, E., Crowther, D. C., Lomas, D. A., & Marciniak, S. J. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70238-7 · Cited by 441 · see citing works
Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease
Butterfield, D. A., & Boyd-Kimball, D. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170543 · Cited by 403 · see citing works
Amyloid β Induces the Morphological Neurodegenerative Triad of Spine Loss, Dendritic Simplification, and Neuritic Dystrophies through Calcineurin Activation
Wu, H.-Y., Hudry, E., Hashimoto, T., Kuchibhotla, K., Rozkalne, A., Fan, Z., Spires-Jones, T., Xie, H., Arbel-Ornath, M., Grosskreutz, C. L., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4456-09.2010 · Cited by 367 · see citing works
The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation
Mairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A., & Polleux, F. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.003 · Cited by 351 · see citing works
PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease
Oksanen, M., Petersen, A. J., Naumenko, N., Puttonen, K., Lehtonen, Š., Gubert Olivé, M., Shakirzyanova, A., Leskelä, S., Sarajärvi, T., Viitanen, M., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.016 · Cited by 332 · see citing works
Calcium Hypothesis of Alzheimer’s disease and brain aging: a framework for integrating new evidence into a comprehensive theory of pathogenesis
Alzheimer's Association Calcium Hypothesis Workgroup, & Khachaturian, Z. S. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.12.006 · Cited by 311 · see citing works
Dysfunction of NMDA receptors in Alzheimer’s disease
Zhang, Y., Li, P., Feng, J., & Wu, M. (2016) · Neurological Sciences · doi:10.1007/s10072-016-2546-5 · Cited by 282 · see citing works
“Besides, Ab is also reported to trigger NMDA-mediated Ca influx, excitotoxicity, and stress-related signaling pathways in neurons which may exacerbate aging-related increases in oxidative stress, impaired energy metabolism, and defective Ca homeostasis [2].”
Background
Oxidative stress and β-amyloid protein in Alzheimer’s disease
Cai, Z., Zhao, B., & Ratka, A. (2011) · NeuroMolecular Medicine · doi:10.1007/s12017-011-8155-9 · Cited by 279 · see citing works
Internalized Tau Oligomers Cause Neurodegeneration by Inducing Accumulation of Pathogenic Tau in Human Neurons Derived from Induced Pluripotent Stem Cells
Usenovic, M., Niroomand, S., Drolet, R. E., Yao, L., Gaspar, R. C., Hatcher, N. G., Schachter, J., Renger, J. J., & Parmentier-Batteur, S. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.1523-15.2015 · Cited by 245 · see citing works
Epigenetic regulation in the pathophysiology of Alzheimer's disease
Chouliaras, L., Rutten, B. P. F., Kenis, G., Peerbooms, O., Visser, P. J., Verhey, F., van Os, J., Steinbusch, H. W. M., & van den Hove, D. L. A. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.002 · Cited by 262 · see citing works
Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II
Djakovic, S. N., Schwarz, L. A., Barylko, B., DeMartino, G. N., & Patrick, G. N. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.021956 · Cited by 236 · see citing works
Soluble forms of tau are toxic in Alzheimer's disease
Kopeikina, K., Hyman, B., & Spires-Jones, T. (2012) · Translational Neuroscience · doi:10.2478/s13380-012-0032-y · Cited by 232 · see citing works
Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease
Blalock, E. M., Buechel, H. M., Popovic, J., Geddes, J. W., & Landfield, P. W. (2011) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2011.06.007 · Cited by 211 · see citing works
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · see citing works
“Release of Ca2+ from the extracellular pools into the cell is mediated by factors such as voltage-gated Ca2+ channels, N-methylo-Daspartate (NMDA) receptors and transient receptor potential channels while intracellular Ca2+, stored in the endoplasmic reticulum, is released via the inositol triphosphate receptor (Ins[1…”
Background
A three-step model for the synaptic recruitment of AMPA receptors
Opazo, P., & Choquet, D. (2011) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2010.08.014 · Cited by 190 · see citing works
Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179 · see citing works
Calcium signalling and Alzheimer's disease
Berridge, M. J. (2011) · Neurochemical Research · doi:10.1007/s11064-010-0371-4 · Cited by 167 · see citing works
BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer’s disease
Chami, L., & Checler, F. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-52 · Cited by 168 · see citing works
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Lane-Donovan, C., & Herz, J. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.12.001 · Cited by 157 · see citing works
“Conversely, expression of CB prevents some of the elevation in resting Ca2+ levels induced by Aβ [59].”
Background
L-type voltage-gated calcium channel blockade with isradipine as a therapeutic strategy for Alzheimer's disease
Anekonda, T. S., Quinn, J. F., Harris, C., Frahler, K., Wadsworth, T. L., & Woltjer, R. L. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.08.020 · Cited by 155 · see citing works
Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model
Li, W., Yu, J., Liu, Y., Huang, X., Abumaria, N., Zhu, Y., Huang, X., Xiong, W., Ren, C., Liu, X.-G., et al. (2014) · Molecular Brain · doi:10.1186/s13041-014-0065-y · Cited by 146 · see citing works
Drug development for alzheimer’s disease: Microglia induced neuroinflammation as a target
Dong, Y., Li, X., Cheng, J., & Hou, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030558 · Cited by 136 · see citing works
Dynamic <sup>11</sup> C-PiB PET Shows Cerebrospinal Fluid Flow Alterations in Alzheimer Disease and Multiple Sclerosis
Schubert, J. J., Veronese, M., Marchitelli, L., Bodini, B., Tonietto, M., Stankoff, B., Brooks, D. J., Bertoldo, A., Edison, P., & Turkheimer, F. E. (2019) · Journal of Nuclear Medicine · doi:10.2967/jnumed.118.223834 · Cited by 121 · see citing works
Physical Exercise and Brain Mitochondrial Fitness: The Possible Role Against <scp>A</scp>lzheimer's Disease
Bernardo, T. C., Marques‐Aleixo, I., Beleza, J., Oliveira, P. J., Ascensão, A., & Magalhães, J. (2016) · Brain Pathology · doi:10.1111/bpa.12403 · Cited by 108 · see citing works
Mitochondrial calcium cycling in neuronal function and neurodegeneration
Walters, G. C., & Usachev, Y. M. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1094356 · Cited by 105 · see citing works
Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice
Zimmermann, H. R., Yang, W., Kasica, N. P., Zhou, X., Wang, X., Beckelman, B. C., Lee, J., Furdui, C. M., Keene, C. D., & Ma, T. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133982 · Cited by 86 · see citing works
Calcium channelopathies and Alzheimer's disease: Insight into therapeutic success and failures
Chakroborty, S., & Stutzmann, G. E. (2014) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.11.012 · Cited by 91 · see citing works
Drug development for Alzheimer’s disease: Review
Lao, K., Ji, N., Zhang, X., Qiao, W., Tang, Z., & Gou, X. (2019) · Journal of drug targeting · doi:10.1080/1061186x.2018.1474361 · Cited by 86 · see citing works
Interneurons, tau and amyloid-β in the piriform cortex in Alzheimer’s disease
Saiz-Sanchez, D., De la Rosa-Prieto, C., Ubeda-Banon, I., & Martinez-Marcos, A. (2015) · Brain Structure and Function · doi:10.1007/s00429-014-0771-3 · Cited by 79 · see citing works
Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains
Sharoar, M. G., Palko, S., Ge, Y., Saido, T. C., & Yan, R. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00464-1 · Cited by 78 · see citing works
The ER and ageing II: Calcium homeostasis
Puzianowska-Kuznicka, M., & Kuznicki, J. (2009) · Ageing Research Reviews · doi:10.1016/j.arr.2009.05.002 · Cited by 73 · see citing works
A Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade
Granzotto, A., Canzoniero, L. M. T., & Sensi, S. L. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.600089 · Cited by 67 · see citing works
The visinin-like proteins VILIP-1 and VILIP-3 in Alzheimer’s disease—old wine in new bottles
Braunewell, K. H. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00020 · Cited by 66 · see citing works
Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer’s disease
Mustaly-Kalimi, S., Gallegos, W., Marr, R. A., Gilman-Sachs, A., Peterson, D. A., Sekler, I., & Stutzmann, G. E. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2211999119 · Cited by 55 · see citing works
Isoform transition from four-repeat to three-repeat tau underlies dendrosomatic and regional progression of neurofibrillary pathology
Hara, M., Hirokawa, K., Kamei, S., & Uchihara, T. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1097-6 · Cited by 55 · see citing works
Etiology of type 2 diabetes and Alzheimer’s disease: Exploring the mitochondria
Silzer, T. K., & Phillips, N. R. (2018) · Mitochondrion · doi:10.1016/j.mito.2018.04.004 · Cited by 53 · see citing works
Cytosolic calcium: Judge, jury and executioner of neurodegeneration in Alzheimer's disease and beyond
Webber, E. K., Fivaz, M., Stutzmann, G. E., & Griffioen, G. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13065 · Cited by 50 · see citing works
Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease
Chiarini, A., Armato, U., Liu, D., & Dal Prà, I. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00134 · Cited by 51 · see citing works
The role of suboptimal mitochondrial function in vulnerability to post‐traumatic stress disorder
Preston, G., Kirdar, F., & Kozicz, T. (2018) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-018-0168-1 · Cited by 36 · see citing works
Clinical Benefits of Antioxidative Supplement Twendee X for Mild Cognitive Impairment: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Prospective Interventional Study
Tadokoro, K., Morihara, R., Ohta, Y., Hishikawa, N., Kawano, S., Sasaki, R., Matsumoto, N., Nomura, E., Nakano, Y., Takahashi, Y., et al. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190644 · Cited by 35 · see citing works
BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex
Petrus, E., & Lee, H.-K. (2014) · Neural Plasticity · doi:10.1155/2014/128631 · Cited by 19 · see citing works
Basis for a neuronal version of Grover's quantum algorithm
Clark, K. B. (2014) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2014.00029 · Cited by 16 · see citing works
MicroRNA Profiling in Aging Brain of PSEN1/PSEN2 Double Knockout Mice
Ham, S., Kim, T. K., Lee, S., Tang, Y.-P., & Im, H.-I. (2018) · Molecular Neurobiology · doi:10.1007/s12035-017-0753-6 · Cited by 12 · see citing works

The Presenilins in Alzheimer's Disease--Proteolysis Holds the Key
Haass, C., & Strooper, B. D. (1999) · Science · doi:10.1126/science.286.5441.916 · Cited by 388 · see citing works
Formation of stable complexes between two Alzheimer's disease gene products: Presenilin-2 and β-amyloid precursor protein
Weidemann, A., Paliga, K., Dürrwang, U., Czech, C., Evin, G. M., Masters, C. L., & Beyreuther, K. T. (1997) · Nature Medicine · doi:10.1038/nm0397-328 · Cited by 211 · see citing works
P1‐069: A PRESENILIN 1 MUTATION ALTERS APP LOCALIZATION IN HUMAN NEURONS
Woodruff, G., Reyna, S. M., & Goldstein, L. S. B. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.05.305
Calpain Activation in Alzheimer's Model Mice Is an Artifact of APP and Presenilin Overexpression
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Authors: Bezprozvanny, I., & Mattson, M. P.
Affiliations: National Institute on Aging (US)
Corresponding author: Mattson, Mark P.
ORCID: Mattson, Mark P.
Venue: Trends in Neurosciences
Publisher: Elsevier BV
Published: 2008-09
Volume: 31
Issue: 9
Pages: 454-463
ISSN: 0166-2236 (ISSN-L)
DOI: 10.1016/j.tins.2008.06.005
PMC: PMC2566585
OpenAlex: W2000075190
Cited by: 938
References: 90
Citations by year: 2026: 33 · 2025: 51 · 2024: 53 · 2023: 57 · 2022: 44 · 2021: 52 · 2020: 50 · 2019: 47 · 2018: 70 · 2017: 54 · 2016: 55 · 2015: 48 · 2014: 47 · 2013: 49 · 2012: 53
FWCI: 6.30
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Trends in Neurosciences (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
National Institute on Aging (Z01AG000312)
National Institute of Neurological Disorders and Stroke (R01NS056224, R01 NS38082, R01NS038082)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: Alzheimer's disease, neuronal calcium homeostasis, calcium mishandling, amyloid-beta, oxidative stress, excitotoxicity, apoptosis, presenilin mutations, endoplasmic reticulum, pore formation, age-related cognitive impairment, energy metabolism
MeSH terms: Alzheimer Disease, Animals, Calcium, Humans, Neurons, Synapses, Signal Transduction, Amyloid beta-Peptides, Calcium Signaling, Presenilins

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Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease

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