Abstract
Calcium is one of the most important intracellular messengers in the brain, being essential for neuronal development, synaptic transmission and plasticity, and the regulation of various metabolic pathways. The findings reviewed in the present article suggest that calcium also plays a prominent role in the pathogenesis of Alzheimer’s disease (AD). Associations between the pathological hallmarks of AD (neurofibrillary tangles [NFT] and amyloid plaques) and perturbed cellular calcium homeostasis have been established in studies of patients, and in animal and cell culture models of AD. Studies of the effects of mutations in the β-amyloid precursor protein (APP) and presenilins on neuronal plasticity and survival have provided insight into the molecular cascades that result in synaptic dysfunction and neuronal degeneration in AD. Central to the neurodegenerative process is the inability of neurons to properly regulate intracellular calcium levels. Increased levels of amyloid β-peptide (Aβ) induce oxidative stress, which impairs cellular ion homeostasis and energy metabolism and renders neurons vulnerable to apoptosis and excitotoxicity. Subtoxic levels of Aβ may induce synaptic dysfunction by impairing multiple signal transduction pathways. Presenilin mutations perturb calcium homeostasis in the endoplasmic reticulum in a way that sensitizes neurons to apoptosis and excitotoxicity; links between aberrant calcium regulation and altered APP processing are emerging. Environmental risk factors for AD are being identified and may include high calorie diets, folic acid insufficiency, and a low level of intellectual activity (bad habits); in each case, the environmental factor impacts on neuronal calcium homeostasis. Low calorie diets and intellectual activity may guard against AD by stimulating production of neurotrophic factors and chaperone proteins. The emerging picture of the cell and molecular biology of AD is revealing novel preventative and therapeutic strategies for eradicating this growing epidemic of the elderly.
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Alberici A., Moratto D., Benussi L., Gasparini L., Ghidoni R., Gatta L. B., et al. (1999) Presenilin 1 protein directly interacts with Bcl-2. J. Biol. Chem. 274, 30,764–30,769.
Babcock D. F., Herrington J., Goodwin P. C., Park Y. B., and Hille B. (1997) Mitochondrial participation in the intracellular Ca2+ network. J. Cell Biol. 136, 833–844.
Barger S. W. and Mattson M. P. (1996) Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer’s β-amyloid precursor. Mol. Brain Res. 40, 116–126.
Barrow P. A., Empson R. M., Gladwell S. J., Anderson C. M., Killick R., Yu X., et al. (2000) Functional phenotype in transgenic mice expressing mutant human presenilin-1. Neurobiol. Dis. 7, 119–126.
Begley J. G., Duan W., Chan S., Duff K., and Mattson M. P. (1999) Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. J. Neurochem. 72, 1030–1039.
Bernardi P., Colonna R., Constantini P., Eriksson O., Fontaine E., Ichas F., et al. (1998) The mitochondrial permeability transition. Biofactors 8, 273–281.
Billingsley M. L., Ellis C., Kincaid R. L., Martin J., Schmidt M. L., Lee V. M., and Trojanowski J. Q. (1994) Calcineurin immunoreactivity in Alzheimer’s disease. Exp. Neurol. 126, 178–184.
Black J. E., Sirevaag A. M., Wallace C. S., Savin M. H., and Greenough W. T. (1989) Effects of complex experience on somatic growth and organ development in rats. Dev. Psychobiol. 22, 727–752.
Blanc E. M., Kelly J. F., Mark R. J., and Mattson M. P. (1997) 4-hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: possible action on Gaq/11. J. Neurochem. 69, 570–580.
Blanc E. M., Keller J. N., Fernandez S., and Mattson M. P. (1998) 4-hydroxynonenal, a lipid peroxidation product, inhibits glutamate transport in astrocytes. Glia 22, 149–160.
Bootman M. D., Collins T. J., Peppiatt C. M., Prothero L. S., MacKenzie L., De Smet P., et al. (2001) Calcium signalling: an overview. Semin. Cell Dev. Biol. 12, 3–10.
Bourguignon L. Y. and Jin H. (1995) Identification of the ankyrin-binding domain of the mouse T-lymphoma cell inositol 1,4,5-trisphosphate (IP3) receptor and its role in the regulation of IP3-mediated internal Ca2+ release. J. Biol. Chem. 270, 7257–7260.
Brillantes A. M., Ondrias B. K., Scott A., Kobrinsky E., Ondriasova E., Moschella M. C., et al. (1999) Stabilization of calcium release channel (ryanodine receptor) function by FK-506 binding protein. Cell 77, 513–523.
Bruce-Keller A. J., Li Y., Lovell M. A., Kraemer P. J., Gary D. S., Brown R. R., et al. (1998) 4-hydroxynonenal, a product of lipid peroxidation, damages cholinergic neurons and impairs visuospatial memory in rats. J. Neuropathol. Exp. Neurol. 57, 257–267.
Bruce-Keller A. J., Umberger G., McFall R., and Mattson M. P. (1999) Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults. Ann. Neurol. 45, 8–15.
Butterfield D. A., Hensley K., Harris M., Mattson M. P., and Carney J. (1994) β-amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem. Biophys. Res. Commun. 200, 710–715.
Buxbaum J. D., Choi E. K., Luo Y., Lilliehook C., Crowley A. C., Merriam D. E., and Wasco W. (1998) Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment. Nature Med. 4, 1177–1181.
Cameron A. M., Steiner J. P., Roskams A. J., Ali S. M., Ronnett G. V., and Snyder S. H. (1996) Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux. Cell 83, 463–472.
Chan S. L., Mayne M., Holden C. P., Geiger J. D., and Mattson M. P. (2000) Presenilin-1 muations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J. Biol. Chem. 275, 18,195–18,200.
Chapman P. F., White G. L., Jones M. W., Cooper-Blacketer D., Marshall V. J., Irizarry M., et al. (1999). Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nature Neurosci. 2, 271–276.
Cheng B. and Mattson M. P. (1992) Glucose deprivation elicits neurofibrillary tangle-like antigenic changes in hippocampal neurons: prevention by NGF and bFGF. Exp. Neurol. 117, 114–123.
Cheng B. and Mattson M. P. (1994) NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults. Brain Res. 640, 56–67.
Choi S. W. and Mason J. B. (2000) Folate and carcinogenesis: an integrated scheme. J. Nutr. 130, 129–132.
Connolly G. P. (1998) Fibroblast models of neurological disorders: fluorescence measurement studies. Trends Pharmacol. Sci. 19, 171–177.
Csordas G. and Hajnoczky G. (2001) Sorting of calcium signals at the junctions of endoplasmic reticulum and mitochondria. Cell Calcium 29, 249–262.
Culmsee C., Zhu Z., Yu Q. S., Chan S. L., Camandola S., Guo Z., Greig N., and Mattson M. P. (2001) A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid β-peptide. J. Neurochem. 77, 220–228.
de la Torre J. C. (2000) Impaired cerebromicrovascular perfusion. Summary of evidence in support of its causality in Alzheimer’s disease. Ann. NY Acad. Sci. 924, 36–152.
De Strooper B., Annaert W., Cupers P., Saftig P., Craessaerts K., Mumm J. S., et al. (1999) A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522.
Duan W. and Mattson M. P. (1999) Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J. Neurosci. Res. 57, 195–206.
Duan W., Guo Z., and Mattson M. P. (2001) Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice. J. Neurochem. 76, 619–626.
Dugan L. L., Sensi S. L., Canzoniero L. M., Handran S. D., Rothman S. M., Goldberg M. P., and Choi D. W. (1995) Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J. Neurosci. 15, 6377–6388.
Dumanchin C., Czech C., Campion D., Cuif M. H., Poyot T., Martin C., et al. (1999) Presenilins interact with Rab11, a small GTPase involved in the regulation of vesicular transport. Hum. Mol. Genet. 8, 1263–1269.
Eckert A., Forstl H., Zerfass R., Hartmann H., and Muller W. E. (1996) Lymphocytes and neutrophils as peripheral models to study the effect of beta-amyloid on cellular calcium signalling in Alzheimer’s disease. Life Sci. 59, 499–510.
Elkind M. S. and Sacco R. L. (1998) Stroke risk factors and stroke prevention. Semin. Neurol. 18, 429–440.
Elliott E., Mattson M. P., Vanderklish P., Lynch G., Chang I., and Sapolsky R. M. (1993) Corticosterone exacerbates kainate-induced alterations in hippocampal tau immunoreactivity and spectrin proteolysis in vivo. J. Neurochem. 61, 57–67.
Estus S., Tucker H. M., van Rooyen C., Wright S., Brigham E. F., Wogulis M., and Rydel R. E. (1997) Aggregated amyloid-beta protein induces cortical neuronal apoptosis and concomitant “apoptotic” pattern of gene induction. J. Neurosci. 17, 7736–7745.
Evans D. A., Hebert L. E., Beckett L. A., Scherr P. A., Albert M. S., Chown M. J., et al. (1997) Education and other measures of socioeconomic status and risk of incident Alzheimer disease in a defined population of older persons. Arch. Neurol. 54, 1399–1405.
Farkas E. and Luiten P. G. (2001) Cerebral microvascular pathology in aging and Alzheimer’s disease. Prog. Neurobiol. 64, 575–611.
Furukawa K., Barger S. W., Blalock E., and Mattson M. P. (1996) Activation of K+ channels and suppression of neuronal activity by secreted β-amyloid precursor protein. Nature 379, 74–78.
Good T. A., Smith D. O., and Murphy R. M. (1996) Betaamyloid peptide blocks the fast inactivating K+ current in rat hippocampal neurons. Biophys. J. 70, 296–304.
Goodman Y. and Mattson M. P. (1994) Secreted forms of β-amyloid precursor protein protect hippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp. Neurol. 128, 1–12.
Goodman Y., Bruce A. J., Cheng B., and Mattson M. P. (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury and amyloid β-peptide toxicity in hippocampal neurons. J. Neurochem. 66, 1836–1844.
Grynspan F., Griffin W. R., Cataldo A., Katayama S., and Nixon R. A. (1997) Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer’s disease. Brain Res. 763, 145–158.
Gunter T. E., Buntinas L., Sparagna G. C., and Gunter K. K. (1998) The Ca2+ transport mechanisms of mitochondria and Ca2+ uptake from physiological-type Ca2+ transients. Biochim. Biophys. Acta 1366, 5–15.
Guo Q., Furukawa K., Sopher B. L., Pham D. G., Robinson N., Martin G. M., and Mattson M. P. (1996) Alzheimer’s PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. Neuro Report 8, 379–383.
Guo G., Sopher B. L., Pham D. G., Furukawa K., Robinson N., Martin G. M., and Mattson M. P. (1997) Alzheimer’s presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid β-peptide: involvement of calcium and oxyradicals. J. Neurosci. 17, 4212–4222.
Guo Q., Christakos S., Robinson N., and Mattson M. P. (1998a) Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function. Proc. Natl. Acad. Sci. USA 95, 3227–3232.
Guo Q., Robinson N., and Mattson M. P. (1998b) Secreted beta-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis. J. Biol. Chem. 273, 12,341–12,351.
Guo Q., Fu W., Sopher B. L., Miller M. W., Ware C. B., Martin G. M., and Mattson M. P. (1999a) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knockin mice. Nature Med. 5, 101–107.
Guo Q., Sebastian L., Sopher B. L., Miller M. W., Glazner G. W., Ware C. B., et al. Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a presenilin-1 mutation. Proc. Natl. Acad. Sci. USA 96, 4125–4130.
Guo Q., Fu W., Holtsberg F. W., Steiner S. M., and Mattson M. P. (1999c) Superoxide mediates the cell-death enhancing action of presenilin-1 mutations. J. Neurosci. Res. 56, 457–470.
Guo Z. and Mattson M. P. (2000) In vivo 2-deoxyglucose administration preserves glucose and glutamate transport and mitochondrial function in cortical synaptic terminals after exposure to amyloid β-peptide and iron: evidence for a stress response. Exp. Neurol. 166, 173–179.
Guo Z., Ersoz A., Butterfield D. A., and Mattson M. P. (2000) Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: preservation of glucose transport and mitochondrial function after exposure to amyloid β-peptide and oxidative and metabolic insults. J. Neurochem. 75, 314–320.
Hajnoczky G., Robb-Gaspers L. D., Seitz M. B., and Thomas A. P. (1995) Decoding of cytosolic calcium oscillations in the mitochondria. Cell 82, 415–424.
Hardy, J. (1997) Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 20, 154–159.
Hendrie H. C., Ogunniyi A., Hall K. S., Baiyewu O., Unverzagt F. W., Gureje O., et al. (2001) Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 285, 739–747.
Hensley K., Carney J. M., Mattson M. P., Aksenova M., Harris M., Wu J. F., et al. (1994) A model for β-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 91, 3270–3274.
Hirsch T., Susin S. A., Marzo I., Marchetti P., Zamzami N., and Kroemer G. (1998) Mitochondrial permeability transition in apoptosis and necrosis Cell. Biol. Toxicol. 14, 141–145.
Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., Yang F., and Cole G. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102.
Ichas F., Jouaville L. S., Sidash S. S., Mazat J. P., and Holmuhamedov E. L. (1994) Mitochondrial calcium spiking: a transduction mechanism based on calcium-induced permeability transition involved in cell calcium signalling. FEBS Lett. 348, 211–215.
Imafuku I., Masaki T., Waragai M., Takeuchi S., Kawabata M., Hirai S., et al. (1999) Presenilin 1 suppresses the function of c-Jun homodimers via interaction with QM/Jif-1. J. Cell Biol. 147, 121–134.
Ingram D. K., Weindruch R., Spangler E. L., Freeman J. R., and Walford R. L. (1987) Dietary restriction benefits learning and motor performance of aged mice. J. Gerontol. 42, 78–81.
Ishida A., Furukawa K., Keller J. N., and Mattson M. P. (1997) Secreted from of β-amyloid precursor protein shifts the frequency dependence for induction of LTD, and enhances LTP in hippocampal slices. Neuro Report 8, 2133–2137.
Jaffe A. B., Toran-Allerand C. D., Greengard P., and Gandy S. E. (1994) Estrogen regulates metabolism of Alzheimer amyloid beta precursor protein. J. Biol. Chem. 269, 13,065–13,068.
Johansson B. B. (1996) Functional outcome in rats transferred to an enriched environment 15 days after focal brain ischemia. Stroke 27, 324–326.
Johnsingh A. A., Johnston J. M., Merz G., Xu J., Kotula L., Jacobsen J. S., and Tezapsidis N. (2000) Altered binding of mutated presenilin with cytoskeletoninteracting proteins. FEBS Lett. 465, 53–58.
Johnson G. V., Cox T. M., Lockhart J. P., Zinnerman M. D., Miller M. L., and Powers R. E. (1997) Transglutaminase activity is increased in Alzheimer’s disease brain. Brain Res. 751, 323–329.
Jones T. A., Chu C. J., Grande L. A., and Gregory A. D. (1999) Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J. Neurosci. 19, 10,153–10,163.
Keller J. N. and Mattson M. P. (1997) 17β-estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity, glucose transport and glutamate transport induced by amyloid β-peptide and iron. J. Neurosci. Res. 50, 522–530.
Keller J. N., Pang Z., Geddes J. W., Begley J. G., Germeyer A., Waeg G., and Mattson M. P. (1997) Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β-peptide: role of the lipid peroxidation product 4-hydroxynonenal. J. Neurochem. 69, 273–284.
Keller J. N., Kindy M. S., Holtsberg F. W., St. Clair D. K., Yen H. C., Germeyer A., et al. (1998a) Mn-SOD prevents neural apoptosis by suppression of peroxynitrite production and consequent lipid peroxidation and mitochondrial dysfunction, and reduces ischemic brain injury in vivo. J. Neurosci. 18, 687–697.
Keller J. N., Guo Q., Holtsberg F. W., Bruce-Keller A. J., and Mattson M. P. (1998) Increased sensitivity to mitochondrial toxin-induced apoptosis in neural cells expressing mutant presenilin-1 is linked to perturbed calcium homeostasis and enhanced oxyradical production. J. Neurosci. 18, 4439–4450.
Kelliher M., Fastbom J., Cowburn R. F., Bonkale W., Ohm T. G., Ravid R., et al. (1999) Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer’s disease neurofibrillary and beta-amyloid pathologies. Neuroscience 92, 499–513.
Kelly J., Furukawa K., Barger S. W., Mark R. J., Rengen M. R., Blanc E. M., et al. (1996) Amyloid β-peptide disrupts carbachol-induced muscarmic cholinergic signal transduction in cortical neurons. Proc. Natl. Acad. Sci. USA 93, 6753–6758.
Kempermann G., Kuhn H. G., and Gage F. H. (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493–495.
Khaodhiar L., McCowen K. C., and Blackburn G. L. (1999) Obesity and its comorbid conditions. Clin. Cornerstone 2, 17–31.
Kleim J. A., Vij K., Ballard D. H., and Greenough W. T. (1997) Learning-dependent synaptic modifications in the cerebellar cortex of the adult rat persist for at least four weeks. J. Neurosci. 17, 717–721.
Kolb B. and Gibb R. (1991) Environmental enrichment and cortical injury: behavioral and anatomical consequences of frontal cortex lesions. Cereb. Cortex 1, 189–198.
Kruman I., Bruce-Keller A. J., Bredesen D. E., Waeg G., and Mattson M. P. (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J. Neurosci. 17, 5097–5108.
Kruman I. I. and Mattson M. P. (1999) Pivotal role of mitochondrial calcium uptake in neuronal cell apoptosis and necrosis. J. Neuroschem. 72, 529–540.
Kruman I., Chan S. L., Culmsee C., Kruman Y., Penix L., and Mattson M. P. (2000) Homocysteine elicits a DNA damage response in neurons resulting in apoptosis and hypersensitivity to excitotoxicity. J. Neurosci. 20, 6920–6926.
Kruman I. I., Kumaravel T.S., Lohani A., Cutler R. G., Kruman Y., Haughey N., Pedersen W. A., Evans M. K., and Mattson M. P. (2001) Folate deficiency and homocysteine enhance amyloid toxicity by impairing DNA repair. Soc. Neurosci. Abstr. 31, 962–969.
Lee J., Bruce-Keller A. J., Kruman Y., Chan S., and Mattson M. P. (1999a) 2-deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: involvement of stress proteins. J. Neurosci. Res. 57, 48–61.
Lee I. M., Hennekens C. H., Berger K., Buring J. E., and Manson J. E. (1999b) Exercise and risk of stroke in male physicians. Stroke 30, 1–6.
Lee C. K., Weindruch R., and Prolla T. A. (2000a) Gene-expression profile of the ageing brain in mice. Nat. Genet. 25, 294–297.
Lee J., Duan W., Long J. M., Ingram D. K., and Mattson M. P. (2000b) Dietary restriction increases survival of newly-generated neural cells and induces BDNF expression in the dentate gyrus of rats. J. Mol. Neurosci. 15, 99–108.
Leissring M. A., Paul B. A., Parker I., Cotman C. W., and LaFerla F. M. (1999) Alzheimer’s presenilin-1 mutation potentiates inositol 1,4,5-trisphosphate-mediated calcium signaling in Xenopus oocytes. J. Neurochem. 72, 1061–1068.
Leissring M. A., Akbari Y., Fanger C. M., Cahalan M. D., Mattson M. P., and LaFerla F. M. (2000) Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J. Cell Biol. 149, 793–798.
Leissring M. A., Yamasaki T. R., Wasco W., Buxbaum J. D., Parker, I., and LaFerla F. M. (2000b) Calsenilin reverses presenilin-mediated enhancement of calcium signaling. Proc. Natl. Acad. Sci USA 97, 8590–8593.
Li Q. X., Evin G., Small D. H., Multhaup G., Beyreuther K., and Masters C. L. (1995) Proteolytic processing of Alzheimer’s disease beta A4 amyloid precursor protein in human platelets. J. Biol. Chem. 270, 14,140–14,147.
Logroscino G., Marder K., Cote L., Tang M. X., Shea S., and Mayeux R. (1996) Dietary lipids and antioxidants in Parkinson’s disease: a population-based, case-control study. Ann. Neurol. 39, 89–94.
Lovell M. A., Ehmann W. D., Mattson M. P., and Markesbery W. R. (1997) Elevated 4-hydroxynonenal levels in ventricular fluid in Alzheimer’s disease. Neurobiol. Aging 18, 457–461.
Lowenstein D. H., Chan P., and Miles M. (1991) The stress protein response in cultured neurons: characterization and evidence for a protective role in excitotoxicity. Neuron 7, 1053–1060.
Lynch T., Cherny R. A., and Bush A. I. (2000) Oxidative processes in Alzheimer’s disease: the role of abetametal interactions. Exp. Gerontol. 35, 445–451.
Mah, A. L., Perry, G., Smith, M. A., and Monteiro, M. J. (2000) Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J. Cell Biol. 151, 847–862.
Mark, R. J., Hensley, K., Butterfield, D. A., and Mattson, M. P. (1995) Amyloid β-peptide impairs ion-motive ATPase activities: evidence for a role in loss of neuronal Ca2+ homeostasis and cell death. J. Neurosci. 15, 6239–6249.
Mark, R. J., Pang, Z., Geddes, J. W., and Mattson, M. P. (1997a) Amyloid β-peptide impairs glucose uptake in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046–1054.
Mark, R. J., Lovell, M. A., Markesbery, W. R., Uchida, K., and Mattson, M. P. (1997b) A role for 4-hydroxynonenal in disruption of ion homeostasis and neuronal death induced by amyloid β-peptide. J. Neurochem. 68, 255–264.
Mark, R. J., Keller, J. N., Kruman, I., and Mattson, M. P. (1997c) Basic FGF attenuates amyloid beta-peptide-induced oxidative stress, mitochondrial dysfunction, and impairment of Na+/K+-ATPase activity in hippocampal neurons. Brain Res. 756, 205–214.
Maruyama, K., Usami, M., Kametani, F., Tomita, T., Iwatsubo, T., Saido, T. C., et al. (2000) Molecular interactions between presenilin and calpain: inhibition of m-calpain protease activity by presenilin-1, 2 and cleavage of presenilin-1 by m-, mu-calpain. Int. J. Mol. Med. 5, 269–273.
Marx, F., Blasko, I., and Grubeck-Loebenstein, B. (1999) Mechanisms of immune regulation in Alzheimer’s disease: a viewpoint. Arch. Immunol. Ther. Exp (Warsz). 47, 205–209.
Mattson, M. P. (1990) Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron 4, 105–117.
Mattson, M. P. (1992) Calcium as sculptor and destroyer of neural circuitry. Exp. Gerontol. 27, 29–49.
Mattson, M. P., Cheng, B., Davis, D., Bryant, K., Lieberburg, I., and Rydel, R. E. (1992) β-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389.
Mattson, M. P., Tomaselli, K., and Rydel, R. E. (1993a) Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF. Brain Res. 621, 35–49.
Mattson, M. P., Cheng, B., Culwell, A., Esch, F., Lieberburg, I., and Rydel, R. E. (1993b) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of β-amyloid precursor protein. Neuron 10, 243–254.
Mattson, M. P. (1994) Secreted forms of β-amyloid precursor protein modulate dendrite outgrowth and calcium responses to glutamate in cultured embryonic hippocampal neurons. J. Neurobiol. 25, 439–450.
Mattson, M. P., Lovell, M. A., Furukawa, K., and Markesbery, W. R. K. (1995) Neurotrophic factors attenuate glutamate-induced accumulation of peroxides, elevation of [Ca2+]i and neurotoxicity, and increase antioxidant enzyme activities in hippocampal neurons. J. Neurochem. 65, 1740–1751.
Mattson, M. P. (1997) Cellular actions of β-amyloid precursor protein, and its soluble and fibrillogenic peptide derivatives. Physiol. Rev. 77, 1081–1132.
Mattson, M. P., Fu, W., Waeg, G., and Uchida, K. (1997) 4-hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. NeuroReport 8, 2275–2281.
Mattson, M. P., Robinson, N., and Guo, Q. (1997) Estrogens stabilize mito chondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1. NeuroReport 8, 3817–3821.
Mattson, M. P. and Duan, W. (1999) Apoptotic biochemical cascades in synaptic compartments: roles in adaptive plasticity and neurodegenerative disorders. J. Neurosci. Res. 58, 152–166.
Mattson, M. P. (2000) Neuroprotective signaling and the aging brain: take away my food and let me run. Brain Res. 886, 47–53.
Mattson, M. P., Zhu, H., Yu, J., and Kindy, M. S. (2000a) Presenilin-1 mutation increases neuronal vulnerability to focal ischemia in vivo, and to hypoxia and glucose dep-rivation in cell culture: involvement of perturbed calcium homeostasis. J. Neurosci. 20, 1358–1364.
Mattson, M. P., LaFerla, F. M., Chan, S. L., Leissring, M., Shepel, P. N., and Geiger, J. D. (2000b) Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 23, 222–229.
Mattson, M. P. and Camandola, S. (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247–254.
Mayeux, R., Costa, R., Bell, K., Merchant, C., Tung, M. X., and Jacobs, D. (1999) Reduced risk of Alzheimer’s disease among individuals with low calorie intake. Neurology 59, S296-S297.
McGeer P. L. and McGeer E. G. (1996) Anti-inflammatory drugs in the fight against Alzheimer’s disease. Ann. N. Y. Acad. Sci. 777, 213–220.
McKee, A. C., Kosik, K. S., Kennedy, M. B., and Kowall, N. W. (1990) Hippocampal neurons predisposed to neurofibrillary tangle formation are enriched in type II calcium/calmodulin-dependent protein kinase. J. Neuropathol. Exp. Neurol. 49, 49–63.
Meldrum, B. S. (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J. Nutr. 130, 1007S-1015S.
Michaelis, E. K. (1998) Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 4, 369–415.
Miller, M. L. and Johnson, G. V. (1995) Transglutaminase cross-linking of the tau protein. J Neurochem. 65, 1760–1770.
Miyata, M. and Smith, J. D. (1996) Apolipoprotein E allelespecific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat. Genet. 14, 55–61.
Murayama, M., Tanaka, S., Palacino, J., Murayama, O., Honda, T., Sun, X., et al. (1998) Direct association of presenilin-1 with beta-catenin. FEBS Lett. 433, 73–77.
Murray, F. E., Landsberg, J. P., Williams, R. J., Esiri, M. M., and Watt, F. (1992) Elemental analysis of neurofibrillary tangles in Alzheimer’s disease using proton-induced X-ray analysis. Ciba. Found. Symp. 169, 201–210.
Nabeshima, T. and Nitta, A. (1994) Memory impairment and neuronal dysfunction induced by β-amyloid protein in rats. Tohoku J. Exp. Med. 174, 241–249.
Naik, U. P., Patel, P. M., and Parise, L. V. (1997) Identification of a novel calcium-binding protein that interacts with the integrin αIIb cytoplasmic domain. J. Biol. Chem. 272, 4651–4654.
Nicholls, D. G. (1985) A role for mitochondria in the protection of cells against calcium overload? Prog. Brain Res. 63, 97–106.
Nilsson, M., Perfilieva, E., Johansson, U., Orwar, O., and Eriksson, P. (1999) Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J. Neurobiol. 39, 569–578.
Nitsch, R. M., Farber, S., Growdon, J. H., and Wurtman, R. J. (1993) Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices. Proc. Natl. Acad. Sci. USA 90, 5191–5193.
Niwa, M., Sidrauski, C., Kaufman, R. J., and Walter, P. (1999) A role for presenilin-1 in nuclear accumulation of Irel fragments and induction of the mammalian unfolded protein response. Cell 99, 691–702.
Nixon, R. A., Saito, K. I., Grynspan, F., Griffin, W. R., Katayama, S., Honda, T., et al. (1994) Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer’s disease. Ann. NY Acad. Sci. 747, 77–91.
Pack-Chung, E., Meyers, M. B., Pettingell, W. P., Moir, R. D., Brownawell, A. M., Cheng, I., et al. (2000) Presenilin 2 interacts with sorcin, a modulator of the ryanodine receptor. J. Biol. Chem. 275, 14440–14445.
Pappolla, M. A., Chyan, Y. J., Omar, R. A., Hsiao, K., Perry, G., Smith, M. A., and Bozner, P. (1998) Evidence of oxidative stress and in vivo neurotoxicity of betaamyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am. J. Pathol. 152, 871–877.
Parent, A., Linden, D. J., Sisodia, S. S., and Borchelt, D. R. (1999) Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1. Neurobiol. Dis. 6, 56–62.
Passer, B. J., Pellegrini, L., Vito, P., Ganjei, J. K., and D’Adamio, L. (1999) Interaction of Alzheimer’s presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death. J. Biol. Chem. 274, 24,007–24,013.
Pedersen, W. A., Chan, S. L., and Mattson, M. P. (2000) A mechanism for the neuroprotective effect of apolipoprotein E: isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal. J. Neurochem. 74, 1426–1433.
Petryniak, M. A., Wurtman, R. J., and Slack, B. E. (1996) Elevated intracellular calcium concentration increases secretory processing of the amyloid precursor protein by a tyrosine phosphorylation-dependent mechanism. Biochem. J. 320, 957–963.
Pickel, V. M., Clarke, C. L., and Meyers, M. B. (1997) Ultrastructural localization of sorcin, a 22 kDa calcium binding protein, in the rat caudate-putamen nucleus: association with ryanodine receptors and intracellular calcium release. J. Comp Neurol 386, 625–634.
Pike, C. J. (1999) Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer’s disease. J. Neurochem. 72, 1552–1563.
Querfurth, H. W. and Selkoe, D. J. (1994) Calcium ionophore increases amyloid beta peptide production by cultured cells. Biochemistry 33, 4550–4561.
Ruck, A., Dolder, M., Wallimann, T., and Brdiczka, D. (1998) Reconstituted adenine nucleotide translocase forms a channel for small molecules comparable to the mitochondrial permeability transition pore. FEBS Lett. 426, 97–101.
Russo-Neustadt, A. A., Beard, R. C., Huang, Y. M., and Cotman, C. W. (2000) Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101, 305–312.
Saito, S., Kobayashi, S., Ohashi, Y., Igarashi, M., Komiya, Y., and Ando, S. (1994) Decreased synaptic density in aged brains and its prevention by rearing under enriched environment as revealed by synaptophysin contents. J. Neurosci. Res. 39, 57–62.
Sayre L. M, Zelasko D. A., Harris P. L., Perry G., Salomon R. G., Smith M. A. (1997) 4-Hydroxynonenal-derived advanced lipid peroxidation end products are increased in Alzheimer’s disease. J. Neurochem. 68, 2092–2097.
Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., et al. (1999) Immunization with amyloidbeta attenuates Alzheimer disease-like pathology in the PDAPP mouse. Nature 400, 173–177.
Scheper, W., Zwart, R., Sluijs, P., Annaert, W., Gool, W. A., and Baas, F. (2000) Alzheimer’s presenilin 1 is a putative membrane receptor for rab GDP dissociation inhibitor. Hum. Mol. Genet. 9, 303–310.
Scott, J. M. and Weir, D. G. (1998) Folic acid, homocysteine and one-carbon methabolism: a review of the essential biochemistry. J. Cardiovasc. Risk 5, 223–227.
Sennvik, K., Benedikz, E., Fastbom, J., Sundstrom, E., Winblad, B., and Ankarcrona, M. (2001) Calcium ionophore A23187 specifically decreases the secretion of betasecretase cleaved amyloid precursor protein during apoptosis in primary rat cortical cultures. J. Neurosci. Res. 63, 429–437.
Shinozaki, K., Maruyama, K., Kume, H., Tomita, T., Saido, T. C., Iwatsubo, T., and Obata, K. (1998) The presenilin 2 loop domain interacts with the mu-calpain C-terminal region. Int. J. Mol. Med. 1, 797–799.
Simpson, P. B. and Russell, J. T. (1998). Role of mitochondrial Ca2+ regulation in neuronal and glial cell signaling. Brain Res. Rev. 26, 72–81.
Smith, P. J., Hammar, K., and Tytell, M. (1995) Effects of exogenous heat shock protein (hsp70) on neuronal calcium flux. Biol. Bull. 189, 209–210.
Smith, S. K., Anderson, H. A., Yu, G., Robertson, A. G., Allen, S. J., Tyler, S. J., et al. (2000) Identification of syntaxin 1A as a novel binding protein for presenilin-1. Mol. Brain Res. 78, 100–107.
Smith-Swintosky, V. L., Pettigrew, C., Craddock, S. D., Culwell, A. R., Rydel, R. E. and Mattson, M. P. (1994) Secreted forms of β-amyloid precursor protein protect against ischemic brain injury. J. Neurochem., 63, 781–784.
Snowdon, D. A., Kemper, S. J., Mortimer, J. A., Greiner, L. H., Wekstein, D. R., and Markesbery, W. R. (1996) Linguistic ability in early life and cognitive function and Alzheimer’s disease in late life. Finding from the Nun Study. JAMA 275, 528–532.
Stabler, S. M., Ostrowski, L. L., Janicki, S. M., and Monteiro, M. J. (1999) Amyristoylated calcium-binding protein that preferentially interacts with the Alzheimer’s disease presenilin 2 protein. J. Cell Biol. 145, 1277–1292.
Stein-Behrens, B., Mattson, M. P., Chang, I., Yeh, M., and Sapolsky, R. (1994) Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus. J. Neurosci. 14, 5373–5380.
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., and Roses, A. D. (1993) Apolipoprotein E: high-avidity binding to beta amyloid and increased frequency of type 4 allele in lateonset familial Alzheimer disease. Proc. Natl. Acad. Sci. USA 90, 1977–1981.
Swain, R.A. and St Clair, L. (1997). The role of folic acid in deficiency states and prevention of disease. J. Fam. Pract. 44, 138–144.
Takashima, A., Murayama, M., Murayama, O., Kohno, T., Honda, T., Yasutake, K., et al. (1998) Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc. Natl. Acad. Sci. USA 95, 9637–41.
Tang, M. X., Jacobs, D., Stern, Y., Marder, K., Schofield, P., Gurland, B., et al. (1996): Effect of oestrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 348: 429–432.
Tolar, M., Keller, J. N., Chan, S. L., Mattson, M. P., Marques, M. A., and Crutcher, K. A. (1999) Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity. J. Neurosci. 19, 7100–7110.
Trejo, J. L., Carro, E., and Torres-Aleman, I. (2001) Circulating insulin-like growth factor I mediates exercise-induced increases in the number of new neurons in the adult hippocampus. J. Neurosci. 21, 1628–1634.
Van Gassen, G., De Jonghe, C., Pype, S., Van Criekinge, W., Julliams, A., Vanderhoeven, I., et al. (1999) Alzheimer’s disease associated presenilin 1 interacts with HC5 and ZETA, subunits of the catalytic 20S proteasome. Neurobiol. Dis. 6, 376–391.
van Praag, H., Kempermann, G., and Gage, F. H. (1999) Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270.
van Rijzingen, I. M., Gispen, W. H., and Spruijt, B. M. (1997) Postoperative environmental enrichment attenuates fimbria-fornix lesion-induced impairments in Morris maze performance. Neurobiol. Learn. Mem. 67, 21–28.
Wang, G. T., Ladror, U. S., Holzman, T. F., Klein, W., and, Krafft, G. A. (1994) Cleavage of fluorogenic substrates for APP-processing proteases by human brain extracts. Ca(2+) substrate interaction is responsible for Ca2+ stimulation of the neural protease activity. Mol. Chem. Neuropathol. 23, 191–199.
Watt, F. (1996) Nuclear microscope analysis in Alzheimer’s and Parkinson’s disease: a review. Cell Mol. Biol 42, 17–26.
Weindruch, R. and Sohal, R. S. (1997) Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N. Engl. J. Med. 337, 986–994.
Wolozin, B., Iwasaki, K., Vito, P., Ganjei, J. K., Lacana, E., Sunderland, T., et al. (1996) Participation of presenilin 2 in apoptosis: enhanced basal activity conferred by an Alzheimer mutation. Science 274, 1710–1713.
Woolley, C. S. and McEwen, B. S. (1994) Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J. Neurosci. 14, 7680–7687.
Wu, X. and Lieber, M. R. (1997) Interaction between DNA-dependent protein kinase and a novel protein, KIP. Mut. Res. 385, 13–20.
Xia, W., Ostaszewski, B. L., Kimberly, W. T., Rahmati, T., Moore, C. L., Wolfe, M. S., and Selkoe, D.J. (2000) FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma secretase cleavage complex. Neurobiol. Dis. 7, 673–681.
Xiao, J., Perry, G., Troncoso, J., and Monteiro, M. J. (1996) alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer’s disease. J. Neuropathol. Exp. Neurol. 55, 954–963.
Xu, X., Shi, Y., Wu, X., Gambetti, P., Sui, D., and Cui, M. Z. (1999) Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus of presenilin-1. J. Biol. Chem. 274, 32,543–32,546.
Tanahashi H., and Tabira T. (2000) Alzheimer’s disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein. Hum. Mol. Genet. 9(15); 2281–2289.
Yamada, M., Miyawaki, A., Saito, K., Nakajima, T., Yamamoto-Hino, M., Ryo, Y., et al. (1995) The calmodulin-binding domain in the mouse type 1 inositol 1,4,5-trisphosphate receptor. Biochem. J. 308, 83–88.
Yankner, B. A. (1996) Mechanisms of neuronal degeneration in Alzheimer’s disease. Neuron 16, 921–932.
Yoo, A. S., Cheng, I., Chung, S., Grenfell, T. Z., Lee, H., Pack-Chung, E., et al. (2000) Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561–572.
Yu, G., Nishimura, M., Arawaka, S., Levitan, D., Zhang, L., Tandon, A., et al. (2000) Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature 407, 48–54.
Yu, Z. F. and Mattson, M. P. (1999) Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: evidence for a preconditioning mechanism. J. Neurosci. Res. 57, 830–839.
Yu, Z., Luo, H., Fu, W., and Mattson, M.P. (1999) The endoplasmic reticulum stress-responsive protein GRP78 protects neurons against excitotoxicity and apoptosis: suppression of oxidative stress and stabilization of calcium homeostasis. Exp. Neurol. 155, 302–314.
Zamparelli, C., Ilari, A., Verzili, D., Giangiacomo, L., Colotti, G., Pascarella, S., and Chiancone, E. (2000) Structure-function relationships of sorcin, a member of the penta EF-hand family: interaction of sorcin fragments with the ryanodine receptor and an Escherichia coli model system. Biochemistry 39, 658–666.
Zhu, H., Guo, Q., and Mattson, M. P. (1999) Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain Res. 842, 224–229.
Zhang W., Han S. W., McKeel D. W., Goate A., and Wu J. Y. Interaction of presenilins with the filamin family of actin-binding proteins. J. Neurosci. 199818(3):914–922.
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Mattson, M.P., Chan, S.L. Dysregulation of cellular calcium homeostasis in Alzheimer’s disease. J Mol Neurosci 17, 205–224 (2001). https://doi.org/10.1385/JMN:17:2:205
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DOI: https://doi.org/10.1385/JMN:17:2:205