• 1
    Ancolio K., Marambaud P., Dauch P. & Checler F. (1997) α-Secretase-derived product of β-amyloid precursor protein is decreased by presenilin 1 mutations linked to familial Alzheimer's disease. J. Neurochem.69,24942499.
  • 2
    Beckman J.S. & Crow J.P. (1993) Pathological implications of nitric oxide, superoxide and peroxynitrite formation.Biochem. Soc. Trans.21,330334.
  • 3
    Behl C., Davis J., Cole G.M. & Schubert D. (1992) Vitamin E protects nerve cells from amyloid beta protein toxicity.Biochem. Biophys. Res. Commun.186,944950.
  • 4
    Behl C., Davis J.B., Lesley R. & Schubert D. (1994) Hydrogen peroxide mediates amyloid β protein toxicity.Cell 77,817827.
  • 5
    Benzi G. & Moretti A. (1997) Contributions of mitochondrial alterations to brain aging.Adv. Cell Aging Gerontol.2,129160.
  • 6
    Bindokas V.P., Jordan J., Lee C.C. & Miller R.J. (1996) Superoxide production in rat hippocampal neurons : selective imaging with hydroethidine.J. Neurosci.16,13241336.
  • 7
    Borchelt D.R., Thinakaran G., Eckman C.B., Lee M.K., Davenport F., Ratovitsky T., Prada C., Kim G., Seekins S., Yager D., Slunt H.H., Wang R., Seeger M., Levey A.I., Gandy S.E., Copeland N.G., Jenkins N.A., Price D.L., Younkin S.G. & Sisodia S.S. (1996) Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-41/1-40 ratio in vitro and in vivo. Neuron 17,10051013.
  • 8
    Brockhaus M., Grunberg J., Rohrig S., Loetscher H., Wittenburg N., Baumeister R., Jacobasen H. & Haass C. (1998) Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling.Neuroreport 9,14811486.
  • 9
    Bruce A.J., Bose S., Fu W., Butt C.M., Mirault E.M., Taniguchi N. & Mattson M.P. (1997) Amyloid β-peptide alters the profile of antioxidant enzymes in hippocampal cultures in a manner similar to that observed in Alzheimer's disease. Pathogenesis 1,1530.
  • 10
    Busciglio J. & Yankner B.A. (1995) Apoptosis and increased generation of reactive oxygen species in Down's syndrome neurons in vitro.Nature 378,776779.
  • 11
    Busciglio J., Lorenzo A., Yeh J. & Yankner B.A. (1995) β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14,879888.
  • 12
    Butterfield D.A., Hensley K., Harris M., Mattson M.P. & 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.200,710715.
  • 13
    Buxbaum J.D., Ruefli A.A., Parker C.A., Cypess A.M. & Greengard P. (1994) Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner.Proc. Natl. Acad. Sci. USA 91,44894493.
  • 14
    Davis J.A., Naruse S., Chen H., Eckman C., Younkin S., Price D.L., Borchelt D.R., Sisodia S.S. & Wong P.C. , (1998) An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos.Neuron 20,603609.
  • 15
    Doan A., Thinakaran G., Borchelt D.R., Slunt H.H., Ratovistsky T., Podlisny M., Selkoe D.J., Seeger M., Gandy S.E., Price D.L. & Sisodia S.S. (1996) Protein topology of presenilin 1.Neuron 17,10231030.
  • 16
    Duff K., Eckman C., Zehr C., Yu X., Prada C., Perez-Tur J., Hutton M., Buee L., Harigaya Y., Yager D., Morgan D., Gordon M.N., Holcomb L., Refolo L., Zenk B., Hardy J. & Younkin S. (1996) Increased amyloid-β42(43) in brains of mice expressing mutant presenilin 1. Nature 383,710713.
  • 17
    Furukawa K., Sopher B.L., Rydel R.E., Begley J.G., Martin G.M., Fox M. & Mattson M.P. (1996) Increased activity-regulating and neuroprotective efficacy of α-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J. Neurochem.67,18821896.
  • 18
    Furukawa K., Fu W., Witke W., Kwiatkowski D.J. & Mattson M.P. (1997) The actin-severing protein gelsolin modulates calcium channel activity and vulnerability to excitotoxicity in hippocampal neurons.J. Neurosci.17,81788186.
  • 19
    Gabuzda D., Busciglio J., Chen L., Matsudaira P. & Yankner B.A. (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative.J. Biol. Chem.269,1362313628.
  • 20
    Gasparini L., Racchi M., Benussi L., Curti D., Binetti G., Bianchetti A., Trabucchi M. & Govoni S. (1997) Effect of energy shortage and oxidative stress on amyloid precursor protein metabolism in COS cells.Neurosci. Lett,231,113117.
  • 21
    Geula C., Wu C.K., Saroff D., Lorenzo A., Yuan M. & Yankner B.A. (1998) Aging renders the brain vulnerable to amyloid β-protein neurotoxicity. Nat. Med.4,827831.
  • 22
    Good P.F., Werner P., Hsu A., Olanow C.W. & Perl D.P. (1996) Evidence of neuronal oxidative damage in Alzheimer's disease.Am. J. Pathol.149,2128.
  • 23
    Goodman Y. & Mattson M.P. (1994) Secreted forms of β-amyloid precursor protein protect nippocampal neurons against amyloid β-peptide-induced oxidative injury. Exp. Neurol 128,112.
  • 24
    Goodman Y. & Mattson M.P. (1996) Ceramide protects hippocampal neurons against excitotoxic and oxidative insults, and amyloid β-peptide toxicity. J. Neurochem.66,869872.
  • 25
    Goodman Y., Bruce A.J., Cheng B. & Mattson M.P. (1996) Estrogens attenuate and corticosterone exacerbates excitotoxicity, oxidative injury and amyloid β-peptide toxicity in hippocampal neurons. J. Neurochem.66,18361844.
  • 26
    Guo Q., Furukawa K., Sopher B.L., Pham D.G., Xie J., Robinson N., Martin G.M. & Mattson M.P. (1996) Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-peptide. Neuroreport 8,379383.
  • 27
    Guo Q., Sopher B.L., Pham D.G., Furukawa K., Robinson N., Martin G.M. & 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.17,41214222.
  • 28
    Guo Q., Christakos S., Robinson N. & Mattson M.P. (1998 a) Calbindin blocks the pro-apoptotic actions of mutant presenilin-1 : reduced oxidative stress and preserved mitochondrial function. Proc. Natl. Acad. Sci. USA 95,32273232.
  • 29
    Guo Q., Fu W., Luo H., SellsS F., Geddes J.W., Bondada V., Rangnekar V.M. & Mattson M.P. (1998 b) Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat. Med. 4,957962
  • 30
    Guo Q., Robinson N. & Mattson M.P. (1998 c) Secreted APPα counteracts the pro-apoptotic action of mutant presenilin-1 by activation of NF-kB and stabilization of calcium homeostasis. J. Biol. Chem.273,1234112351.
  • 31
    Guo Q., Fu W., Sopher B.L., Miller M.W., Ware C.B., Martin G.M. & Mattson M.P. (1999) Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knockin mice.Nat. Med. (in press).
  • 32
    Hardy J. (1997) Amyloid, the presenilins and Alzheimer's disease.Trends Neurosci.20,154159.
  • 33
    Hooper D.C., Spitsin S., Kean R.B., Champion J.M., Dickson G.M., Chaudhry I. & Koprowski H. (1998) Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis.Proc. Natl. Acad. Sci. USA 95 675680.
  • 34
    Hu J. & -Fakahany E.E. (1993) β-Amyloid 25-35 activates nitric oxide synthase in a neuronal clone. Neuroreport 4,760762.
  • 35
    Janicki S. & Monteiro M.J. (1997) Increased apoptosis arising from increased expression of the Alzheimer's disease-associated presenilin-2 mutation (N141I).J. Cell Biol.139,485495.
  • 36
    Keller J.N., Pang Z., Geddes J.W., Begley J.G., Germeyer A., Waeg G. & 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.69,273284.
  • 37
    Keller J.N., Kindy M.S., Holtsberg F.W., Clair D.K., Yen H.C., Germeyer A., Steiner S.M., Bruce-Keller A.J., Hutchins J.B. & Mattson M.P. (1998) Mitochondrial MnSOD prevents neural apoptosis and reduces ischemic brain injury : suppression of peroxynitrite production, lipid peroxidation and mitochondrial dysfunction.J. Neurosci.18,687697.
  • 38
    Kim T.W. & Tanzi R.E. (1997) Presenilins and Alzheimer's disease.Curr. Opin. Neurobiol.7,683688.
  • 39
    Kim T., Pettingell W.H., Jung Y., Kovasc D.M. & Tanzi R.E. (1997) Alternative cleavage of Alzheimer-associated presenilins during apoptosis by a caspase-3 family protease.Science 277,373376.
  • 40
    Kooy N.W., Royall J.A., Ischiropoulos H. & Beckman J.S. (1994) Peroxynitrite-mediated oxidation of dihydrorhodamine 123.Free Radic. Biol. Med.16,149156.
  • 41
    Kovacs D.M., Fausett H.J., Page K.J., Kim T., Moir R.D., Merriam D.E., Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T., Tanzi R.E. & Wasco W. (1996) Alzheimer-associated presenilins 1 and 2 : neuronal expression in brain and localization to intracellular membranes in mammalian cells.Nat. Med.2,224229.
  • 42
    Kroemer G., Zamzami N. & Susin S.A. (1997) Mitochondrial control of apoptosis.Immunol. Today 18,4451.
  • 43
    Kruman I., Bruce-Keller A.J., Bredesen D.E., Waeg G. & Mattson M.P. (1997) Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis.J. Neurosci.17,50975108.
  • 44
    Lafon-Cazal M., Pietri S., Cuicasi M. & Bockaert J. (1993) NMDA-dependent superoxide production and neurotoxicity.Nature 364,535537.
  • 45
    Lehmann S., Chiesa R. & Harris D.A. (1997) Evidence for a six-transmembrane domain structure of presenilin 1.J. Biol. Chem.272,1204712051.
  • 46
    Loo D., Copani A., Pike C., Whittemore E., Walencewicz A. & Cotman C.W. (1993) Apoptosis is induced by β-amyloid in cultured central nervous system neurons. Proc. Natl. Acad. Sci. USA 90,79517955.
  • 47
    Lovell M.A., Ehmann W.D., Mattson M.P. & Markesbery W.R. (1997) Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease.Neurobiol. Aging 18,457461.
  • 48
    Mark R.J., Hensley K., Butterfield D.A. & 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.15,62396249.
  • 49
    Mark R.J., Blance E.M. & Mattson M.P. (1996) Amyloid β-peptide and oxidative cell injury in Alzheimer's disease. Mol. Neurobiol.12,211224.
  • 50
    Mark R.J., Lovell M.A., Markesbery W.R., Uchida K. & Mattson M.P. (1997 a) A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid β-peptide. J. Neurochem.68,255264.
  • 51
    Mark R.J., Pang Z., Geddes J.W. & Mattson M.P. (1997 b) Amyloid β-peptide impairs glucose uptake in hippocampal and cortical neurons : involvement of membrane lipid peroxidation. J. Neurosci. 17,10461054.
  • 52
    Mattson M.P. (1990) Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and calcium influx in cultured hippocampal neurons.Neuron 4,105117.
  • 53
    Mattson M.P. (1997) Cellular actions of β-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol. Rev. 77,10811132.
  • 54
    Mattson M.P., Cheng B., Davis D., Bryant K., Lieberburg I. & Rydel R.E. (1992) β-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12,376389.
  • 55
    Mattson M.P., Barger S.W., Cheng B., Lieberburg I., Smith-Swintosky V.L. & Rydel R.E. (1993) β-Amyloid precursor protein metabolites and loss of neuronal calcium homeostasis in Alzheimer's disease. Trends Neurosci. 16,409415.
  • 56
    Mattson M.P.G, Luo H., Fu W. & Furukawa K. (1997 a) Activation of NF-kB protects hippocampal neurons against oxidative stress-induced apoptosis : evidence for induction of Mn-SOD and suppression of peroxynitrite production and protein tyrosine nitration. J. Neurosci. Res. 49,681697.
  • 57
    Mattson M.P., Robinson N., and Guo Q. (1997 b) Estrogens stabilize mitochondrial function and protect neural cells against the pro-apoptotic action of mutant presenilin-1. Neuroreport 8,38173821.
  • 58
    Mattson M.P., Fu W., Waeg G. & Uchida K. (1997 c) 4-Hydroxynonenal, a product of lipid peroxidation, inhibits dephosphorylation of the microtubule-associated protein tau. Neuroreport 8,22752281.
  • 59
    Mattson M.P., Guo Q., Furukawa K., and Pedersen W.A. (1998 a) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer's disease. J. Neurochem. 70,114.
  • 60
    Mattson M.P., Keller J.N. & Begley J.G. (1998 b) Evidence for synaptic apoptosis. Exp. Neurol. 153,3548.
  • 61
    Mecocci P., MacGarvey M.S. & Beal M.F. (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease.Ann. Neurol. 36,747751.
  • 62
    Miller D.K. (1997) The role of the caspase family of cysteine proteases in apoptosis.Semin. Immunol. 9,3549.
  • 63
    Otvos L., Szendrei G.I., Lee V.M. & Mantsch H.H. (1993) Human and rodent Alzheimer β-amyloid peptides acquire distinct conformations in membrane-mimicking solvents. Eur. J. Biochem. 211,249257.
  • 64
    Qian S., Jiang P., Guan X.M., Singh G., Trumbauer M.E., Yu H., Chen H.Y., Van de Ploeg L.H. & Zheng H. (1998) Mutant human presenilin 1 protects presenilin 1 null mouse against embryonic lethality and elevates Aβ1-42/43 expression. Neuron 20,611617.
  • 65
    Querfurth H.W. & Selkoe D.J. (1994) Calcium ionophore increases amyloid β peptide production by cultured cells.Biochemistry 33,45504561.
  • 66
    Sano M., Ernesto C., Thomas R.G., Klauber M.R., Schafer K., Grundman M., Woodbury P., Growdon J., Cotman C.W., Pfeiffer E., Schneider L.S. & Thal L.J. (1997) A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 336,12161222.
  • 67
    Sayre L.M., Zelasko D.A., Harris P.L.R., 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.68,20922097.
  • 68
    Scheuner D., Eckman C., Jensen M., Song X., Citron M., Suzuki N., Bird T.D., Hardy J., Hutton M., Kukull W., Larson E., Levy-Lahad E., Viitanen M., Peskind E., Poorkaj P., Schellenberg G., Tanzi R., Wasco W., Lannfelt L., Selkoe D. & Younkin S. (1996) The amyloid β protein deposited in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.Nat. Med. 2,864870.
  • 69
    Shen J., Bronson R.T., Chen D.F., Xia W., Selkoe D.J. & Tonegawa S. (1997) Skeletal and CNS defects in presenilin-1-deficient mice.Cell 89,629639.
  • 70
    Smith C.D., Carney J.M., Starke-Reed P.E., Oliver C.N., Stadtman E.R., Floyd R.A. & Markesbery W.R. (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.Proc. Natl. Acad. Sci. USA 88,1054010543.
  • 71
    Smith M.A., Harris P.L.R., Sayre L.M., Backman J.S. & Peryy G. (1997) Widespread peroxynitrite-mediated damage in Alzheimer's disease.J. Neurosci. 14,53735380.
  • 72
    Stein-Behrens B., Mattson M.P., Chang I., Yeh M. & Saplosky R.M. (1994) Stress exacerbates neuron loss and cytoskeletal pathology in the hippocampus.J. Neurosci.14,53735380.
  • 73
    Su J.H., Anderson A.J., Cummings B. & Cotman C.W. (1994) Immunocytochemical evidence for apotosis in Alzheimer's disease.Neuroreport 5,25292533.
  • 74
    Su J.H., Deng G. & Cotman C.W. (1997) Neuronal DNA damage precedes tangle formation and is associated with up-regulation of nitrotyrosine in Alzheimer's disease brain.Brain Res. 774,193199.
  • 75
    Tang M.X., Jacobs D., Stern Y., Marder K., Schofield P., Gurland B., Andrews H. & Mayeux R. (1996) Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease.Lancet 348,429432.
  • 76
    Walter J., Capell A., Grunberg J., Pesold B., Schindzielorz A., Prior R., Podlinsy M.B., Fraser P., George-Hyslop P., Selkoe D.J. & Haass C. (1996) The Alzheimer's disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum.Mol. Med. 2,673691.
  • 77
    Wolozin B., Iwasaki K., Vito P., Ganjei J.K., Lacana E., Sunderland T., Zhao B., Kusiak J.W., Wasco W. & D'Adamio L. (1996) Participation of presenilin 2 in apoptosis : enhanced basal activity conferred by an Alzheimer mutation.Science 274,17101713.
  • 78
    Wong P.C., Zheng H., Chen H., Becher M.W., Sirinathsinghji D.J.S.T, Chen H.Y., Price D.L., Van der Ploeg L.H.T. & Sisodia S.S. (1997) Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387,288292.
  • 79
    Yankner B.A. (1996) Mechanisms of neuronal degeneration in Alzheimer's disease.Neuron 16,921932.
  • 80
    Yu Z.F., Bruce-Keller A.J., Goodman Y. & Mattson M.P. (1998) Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo.J. Neurosci. Res. 53,613625.