Possible Causes of Alzheimer's Disease: Amyloid Fragments, Free Radicals, and Calcium Homeostasis

Alzheimer's disease (AD) is a form of dementia in which patients develop neurodegeneration and complete loss of cognitive abilities and die prematurely. No treatment is known for this condition. Evidence points toward beta-amyloid as one of the main causes for cytotoxic processes. The cascade of biochemical events that lead to neuronal death appears to be interference with intracellular calcium homeostasis via activation of calcium channels, intracellular calcium stores, and subsequent production of free radicals by calcium-sensitive enzymes. The glutamatergic system seems to be implicated in mediating the toxic processes. Several strategies promise amelioration of neurodegenerative developments as judging from in vitro experiments. Glutamate receptor-selective drugs, antioxidants, inhibitors of nitric oxide synthase, calcium channel antagonists, receptor or enzyme inhibitors, and growth factors promise help. Especially combinations of drugs that act at different levels might prolong patients' health.

[1]  M. Mattson Neuroprotective Signal Transduction: Relevance to Stroke , 1997, Neuroscience & Biobehavioral Reviews.

[2]  M. Mattson,et al.  β-Amyloid precursor protein and alzheimer's disease: The peptide plot thickens , 1992, Neurobiology of Aging.

[3]  K. Flanders,et al.  Transforming growth factors-β protect primary rat hippocampal neuronal cultures from degeneration induced by β-amyloid peptide , 1996, Brain Research.

[4]  J. Disterhoft,et al.  Calcium hypothesis of aging and dementia , 1994 .

[5]  A. Privat,et al.  Reversion of β25–35-amyloid peptide-induced amnesia by NMDA receptor-associated glycine site agonists , 1996, Brain Research.

[6]  J. Haines,et al.  ApoE-4 and Age at Onset of Alzheimer's Disease , 1997, Neurology.

[7]  R. Anwyl,et al.  HFS-induced long-term potentiation and LFS-induced depotentiation in area CA1 of the hippocampus are not good models for learning , 1997, Psychopharmacology.

[8]  D. Borchelt,et al.  Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins , 1995, Neuron.

[9]  Y. Oyama,et al.  Change in membrane permeability induced by amyloid beta-protein fragment 25-35 in brain neurons dissociated from rats. , 1995, Japanese journal of pharmacology.

[10]  T. Bliss,et al.  A synaptic model of memory: long-term potentiation in the hippocampus , 1993, Nature.

[11]  G. Cole,et al.  Effects of injected Alzheimer beta-amyloid cores in rat brain. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Cowburn,et al.  β-amyloid peptides enhance binding of the calcium mobilising second messengers, inositol(1,4,5)trisphosphate and inositol-(1,3,4,5)tetrakisphosphate to their receptor sites in rat cortical membranes , 1995, Neuroscience Letters.

[13]  M. Mattson Degenerative and protective signaling mechanisms in the neurofibrillary pathology of AD , 1995, Neurobiology of Aging.

[14]  K. Whitehead,et al.  Inhibition of nitric oxide synthase by 1‐(2‐trifluoromethylphenyl) imidazole (TRIM) in vitro: antinociceptive and cardiovascular effects , 1996, British journal of pharmacology.

[15]  M. Sporn,et al.  Inducible nitric oxide synthase in tangle-bearing neurons of patients with Alzheimer's disease , 1996, The Journal of experimental medicine.

[16]  L. Iversen,et al.  Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia. , 1984, Brain : a journal of neurology.

[17]  D. Selkoe,et al.  Interaction between amyloid precursor protein and presenilins in mammalian cells: implications for the pathogenesis of Alzheimer disease. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. Iadecola Bright and dark sides of nitric oxide in ischemic brain injury , 1997, Trends in Neurosciences.

[19]  S. Doré,et al.  Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases. , 1997, Trends in neurosciences.

[20]  M. Moskowitz,et al.  Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. , 1994, Science.

[21]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[22]  F. Murad,et al.  Ca2+/calmodulin-regulated nitric oxide synthases. , 1992, Cell calcium.

[23]  P. Aisen,et al.  Maturational Regulation and Regional Induction of Cyclooxygenase-2 in Rat Brain: Implications for Alzheimer's Disease , 1997, Experimental Neurology.

[24]  W R Markesbery,et al.  Oxidative stress hypothesis in Alzheimer's disease. , 1997, Free radical biology & medicine.

[25]  C. Bieberich,et al.  The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice , 1995, Nature Genetics.

[26]  M. Mattson Calcium and Neuronal Injury in Alzheimer's Disease , 1994, Annals of the New York Academy of Sciences.

[27]  D. Price,et al.  Generation of APLP2 KO Mice and Early Postnatal Lethality in APLP2/APP Double KO Mice , 1997, Neurobiology of Aging.

[28]  C. Masters,et al.  The Role of Heparan Sulfate Proteoglycans in the Pathogenesis of Alzheimer's Disease a , 1996, Annals of the New York Academy of Sciences.

[29]  L. Mucke,et al.  Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein , 1995, Nature.

[30]  L. Giovannelli,et al.  Differential effects of amyloid peptides β-(1–40) and β-(25–35) injections into the rat nucleus basalis , 1995, Neuroscience.

[31]  Y. Kitamura,et al.  Changes of p53 in the brains of patients with Alzheimer's disease. , 1997, Biochemical and biophysical research communications.

[32]  M. Mattson,et al.  Calcium-destabilizing and neurodegenerative effects of aggregated β-amyloid peptide are attenuated by basic FGF , 1993, Brain Research.

[33]  M. Mullan,et al.  Superoxide free radical and intracellular calcium mediate Aβ 1–42 induced endothelial toxicity , 1997, Brain Research.

[34]  E. Rojas,et al.  The Ability of Amyloid β‐Protein [AβP (1–40)] to Form Ca2+ Channels Provides a Mechanism for Neuronal Death in Alzheimer's Disease , 1994 .

[35]  L. Colom,et al.  Cell death induced by β-amyloid 1–40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis , 1995, Brain Research.

[36]  S. Younkin,et al.  An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. , 1994, Science.

[37]  H. Edelberg,et al.  The biology of Alzheimer's disease , 1996, Mechanisms of Ageing and Development.

[38]  J F Disterhoft,et al.  The Calcium Rationale in Aging and Alzheimer's Disease , 1994, Annals of the New York Academy of Sciences.

[39]  M. Smith,et al.  Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer's disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. , 1998, The American journal of pathology.

[40]  D. Graham,et al.  Apolipoprotein E ε4 allele is associated with deposition of amyloid β-protein following head injury , 1995, Nature Medicine.

[41]  E. Masliah,et al.  nNOS Expressing Neurons in the Entorhinal Cortex and Hippocampus Are Affected in Patients with Alzheimer's Disease , 1998, Experimental Neurology.

[42]  S. Takashima,et al.  Induction of cyclo‐oxygenase 2 in brains of patients with Down's syndrome and dementia of Alzheimer type: specific localization in affected neurones and axons , 1997, Neuroreport.

[43]  C. Hölscher Nitric oxide, the enigmatic neuronal messenger: its role in synaptic plasticity , 1997, Trends in Neurosciences.

[44]  M. Pericak-Vance,et al.  Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Mattson,et al.  Ceramide Protects Hippocampal Neurons Against Excitotoxic and Oxidative Insults, and Amyloid β‐Peptide Toxicity , 1996, Journal of neurochemistry.

[46]  W. K. Cullen,et al.  β‐Amyloid produces a delayed NMDA receptor‐ dependent reduction in synaptic transmission in rat hippocampus , 1996, Neuroreport.

[47]  M. Harrigan,et al.  Beta amyloid is neurotoxic in hippocampal slice cultures , 1995, Neurobiology of Aging.

[48]  P. Mcgeer,et al.  Anti‐Inflammatory Drugs in the Fight against Alzheimer's Disease a , 1996, Annals of the New York Academy of Sciences.

[49]  E. Masliah,et al.  Deficient glutamate tranport is associated with neurodegeneration in Alzheimer's disease , 1996 .

[50]  P. Gluckman,et al.  Bax expression in mammalian neurons undergoing apoptosis, and in Alzheimer's disease hippocampus , 1997, Brain Research.

[51]  Brian J Cummings,et al.  beta-Amyloid induces neuritic dystrophy in vitro: similarities with Alzheimer pathology. , 1992, Neuroreport.

[52]  J. Growdon,et al.  Role of neurotransmission in the regulation of amyloid beta-protein precursor processing. , 1994, Biochemical pharmacology.

[53]  C. Hölscher Prostaglandins play a role in memory consolidation in the chick. , 1995, European journal of pharmacology.

[54]  H. Gertz,et al.  Cortical distribution of neurofibrillary tangles in Alzheimer's disease matches the pattern of neurons that retain their capacity of plastic remodelling in the adult brain , 1998, Neuroscience.

[55]  S. Younkin,et al.  Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. , 1993, Science.

[56]  Carl W. Cotman,et al.  In vitro aging of ß-amyloid protein causes peptide aggregation and neurotoxicity , 1991, Brain Research.

[57]  M. Mattson Mother's legacy: mitochondrial DNA mutations and Alzheimer's disease. , 1997, Trends in neurosciences.

[58]  C. Masters,et al.  Secretion of nerve growth factor from septum stimulates neurite outgrowth and release of the amyloid protein precursor of Alzheimer's disease from hippocampal explants , 1994, Journal of neuroscience research.

[59]  J. Panetta,et al.  Neuroprotective effects of the antioxidant LY231617 and NO synthase inhibitors in global cerebral ischaemia , 1997, Brain Research.

[60]  C. Marra,et al.  Effects of aging and of Alzheimer's disease on verbal memory. , 1995, Journal of clinical and experimental neuropsychology.

[61]  Toru Shimizu,et al.  Clinical comparison of Alzheimer's disease in pedigrees with the codon 717 Val→Ile mutation in the amyloid precursor protein gene , 1993, Neurobiology of Aging.

[62]  F. Nicoletti,et al.  Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide. , 1995, Molecular pharmacology.

[63]  K. M. Uchida,et al.  Donepezil: an anticholinesterase inhibitor for Alzheimer's disease. , 1997, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[64]  Mark P. Mattson,et al.  β-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease , 1993, Trends in Neurosciences.

[65]  D. K. Rush,et al.  Intracerebral /sB-amyloid(25–35) produces tissue damage: Is it neurotoxic? , 1992, Neurobiology of Aging.

[66]  M. Mattson,et al.  Alzheimer's PS‐1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β‐peptide , 1996, Neuroreport.

[67]  Yan Zhou,et al.  Actions of Neurotoxic β‐Amyloid on Calcium Homeostasis and Viability of PC12 Cells Are Blocked by Antioxidants but Not by Calcium Channel Antagonists , 1996 .

[68]  M. Beal,et al.  In vivo neurotoxicity of beta-amyloid [β(1–40)] and the β(25–35) fragment , 1992, Neurobiology of Aging.

[69]  I. Lieberburg,et al.  Lack of alzheimer pathology after β-amyloid protein injections in rat brain , 1992, Neurobiology of Aging.

[70]  Y. Nakashima,et al.  Free radicals and superoxide dismutase in blood of patients with Alzheimer's disease and vascular dementia , 1997, Journal of the Neurological Sciences.

[71]  K. Beyreuther,et al.  APP Gene Family Alternative Splicing Generates Functionally Related Isoforms a , 1996, Annals of the New York Academy of Sciences.

[72]  H. Brewer,et al.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments , 1994, Nature.

[73]  B. Greenberg,et al.  APP transgenesis: Approaches toward the development of animal models for Alzheimer disease neuropathology , 1996, Neurobiology of Aging.

[74]  E. El-Fakahany,et al.  beta-Amyloid 25-35 activates nitric oxide synthase in a neuronal clone. , 1993, Neuroreport.

[75]  M. D. Gooch,et al.  Molecular basis of Alzheimer's disease. , 1996, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[76]  R. Wurtman,et al.  Metabotropic Glutamate Receptor Subtype mGluR1α Stimulates the Secretion of the Amyloid β‐Protein Precursor Ectodomain , 1997 .

[77]  J. Schnabel New Alzheimer's therapy suggested. , 1993, Science.

[78]  W. Horton,et al.  Expression of mutant amyloid precursor proteins induces apoptosis in PC12 cells , 1997, Journal of neuroscience research.

[79]  R. Katzman.,et al.  Editorial: The prevalence and malignancy of Alzheimer disease. A major killer. , 1976, Archives of neurology.

[80]  R. Sapolsky,et al.  Failure of beta-amyloid protein fragment 25–35 to cause hippocampal damage in the rat , 1992, Neurobiology of Aging.

[81]  J. Growdon,et al.  Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. , 1992, Science.

[82]  J. Kanfer,et al.  Amyloid beta protein (25–35) stimulation of phospholipases A, C and D activities of LA‐N‐2 cells , 1995, FEBS letters.

[83]  D. Perl,et al.  Evidence of neuronal oxidative damage in Alzheimer's disease. , 1996, The American journal of pathology.

[84]  B. Yankner,et al.  Amyloid Fibril Toxicity in Alzheimer's Disease and Diabetes a , 1996, Annals of the New York Academy of Sciences.

[85]  R. Anwyl,et al.  beta-Amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus. , 1995, Neuroreport.

[86]  M. Mattson,et al.  Activation of K+ channels and suppression of neuronal activity by secreted β-amyloid-precursor protein , 1996, Nature.

[87]  D. Carter,et al.  Ibuprofen: effect on inducible nitric oxide synthase. , 1997, Brain research. Molecular brain research.

[88]  N. Cairns,et al.  An Assessment of Oxidative Damage to Proteins, Lipids, and DNA in Brain from Patients with Alzheimer's Disease , 1997, Journal of neurochemistry.

[89]  P. Eikelenboom,et al.  Inflammatory mechanisms in Alzheimer's disease. , 1994, Trends in pharmacological sciences.

[90]  M. Weiner Alzheimer's Disease: Diagnosis and Treatment , 1997, Harvard review of psychiatry.

[91]  Kenneth Maiese,et al.  Nitric oxide: a downstream mediator of calcium toxicity in the ischemic cascade , 1994, Neuroscience Letters.

[92]  Alan S. Perelson,et al.  Decay characteristics of HIV-1-infected compartments during combination therapy , 1997, Nature.

[93]  L. Mucke,et al.  Neurotrophic and Neuroprotective Effects of hAPP in Transgenic Mice a , 1996, Annals of the New York Academy of Sciences.

[94]  F. Holsboer,et al.  High Constitutive NFk B Activity Mediates Resistance to Oxidative Stress in Neuronal Cells , 1998 .

[95]  M. Mullan,et al.  β-Amyloid-mediated vasoactivity and vascular endothelial damage , 1996, Nature.

[96]  C. Overly,et al.  Individual isoforms of the amyloid βprecursor protein demonstrate differential adhesive potentials to constituents of the extracellular matrix , 1997, Journal of neuroscience research.

[97]  H. Braak,et al.  Alzheimer’s disease: transiently developing dendritic changes in pyramidal cells of sector CA1 of the Ammon’s horn , 1997, Acta Neuropathologica.

[98]  A. Privat,et al.  Inhibitors of free radical formation fail to attenuate direct β‐amyloid25–35 peptide‐mediated neurotoxicity in rat hippocampal cultures , 1994, Journal of neuroscience research.

[99]  M. Rowan,et al.  l-AP4 (l-(+)-2-amino-4-phosphonobutyric acid) induced impairment of spatial learning in the rat is antagonized by MAP4 ((S)-2-amino-2methyl-4-phosphonobutanoic acid) , 1996, Behavioural Brain Research.

[100]  P. May,et al.  β-amyloid peptide in vitro toxicity: Lot-to-lot variability , 1992, Neurobiology of Aging.

[101]  C. Gray,et al.  Neurodegeneration mediated by glutamate and β-amyloid peptide: a comparison and possible interaction , 1995, Brain Research.

[102]  J. Schulz,et al.  Inhibition of Neuronal Nitric Oxide Synthase by 7‐Nitroindazole Protects Against MPTP‐Induced Neurotoxicity in Mice , 1995, Journal of neurochemistry.

[103]  M. Mattson,et al.  Role of Cyclic GMP in the Regulation of Neuronal Calcium and Survival by Secreted Forms of β‐Amyloid Precursor , 1995, Journal of neurochemistry.

[104]  P. Greengard,et al.  Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[105]  D. Sirinathsinghji,et al.  Mice Deficient for the Amyloid Precursor Protein Gene , 1996, Annals of the New York Academy of Sciences.

[106]  L. S. Perlmutter,et al.  β-Amyloid induces apoptosis in human-derived neurotypic SH-SY5Y cells , 1996, Brain Research.

[107]  Bruce A. Yankner,et al.  Methodological variables in the assessment of beta amyloid neurotoxicity , 1992, Neurobiology of Aging.

[108]  M. Memo,et al.  Opposing regulation of amyloid precursor protein by ionotropic and metabotropic glutamate receptors. , 1995, Neuroreport.

[109]  F. Jiménez-Jiménez,et al.  The Role of Nitric Oxide in Neurodegeneration , 1998, Drugs & aging.

[110]  R. Wurtman,et al.  Metabotropic Glutamate Receptors Regulate APP Processing in Hippocampal Neurons and Cortical Astrocytes Derived from Fetal Rats a , 1996, Annals of the New York Academy of Sciences.

[111]  L. Horrocks,et al.  Involvement of glutamate receptors, lipases, and phospholipases in long‐term potentiation and neurodegeneration , 1994, Journal of neuroscience research.

[112]  S H Snyder,et al.  Biological roles of nitric oxide. , 1992, Scientific American.

[113]  J. Trojanowski,et al.  Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain , 1997, The Journal of Neuroscience.

[114]  C. Albanese,et al.  Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NFκB-dependent mechanism , 1998 .

[115]  G. Ronquist,et al.  Alzheimer amyloid β‐peptides exhibit ionophore‐like properties in human erythrocytes , 1995, European journal of clinical investigation.

[116]  E. Mufson,et al.  Cellular Delivery of NGF Does Not Alter the Expression of β-Amyloid Immunoreactivity in Young or Aged Nonhuman Primates , 1997, Experimental Neurology.

[117]  T Vogel,et al.  Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. , 1994, The American journal of pathology.

[118]  V. Bigl,et al.  Glutamate-stimulated secretion of amyloid precursor protein from cortical rat brain slices , 1997, Neurochemistry International.

[119]  K. Kawasaki,et al.  Amyloid β Protein Potentiates Ca2+ Influx Through L‐Type Voltage‐Sensitive Ca2+ Channels: A Possible Involvement of Free Radicals , 1997, Journal of neurochemistry.

[120]  P. Greengard,et al.  Immunocytochemical localization of amyloid precursor protein in rat brain , 1994, The Journal of comparative neurology.

[121]  P. Mcgeer,et al.  β‐Amyloid protein enhances macrophage production of oxygen free radicals and glutamate , 1997 .

[122]  C. Regan,et al.  Intraventricular infusions of antibodies to amyloid-β-protein precursor impair the acquisition of a passive avoidance response in the rat , 1990, Neuroscience Letters.

[123]  H. Kimura,et al.  Amyloid β Toxicity Consists of a Ca2+‐Independent Early Phase and a Ca2+‐Dependent Late Phase , 1996 .

[124]  A. M. Saunders,et al.  Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease , 1994, Nature Genetics.

[125]  M. Mattson,et al.  Basic FGF attenuates amyloid β-peptide-induced oxidative stress, mitochondrial dysfunction, and impairment of Na+/K+-ATPase activity in hippocampal neurons , 1997, Brain Research.

[126]  A. Privat,et al.  In vitro aggregation facilitates β-amyloid peptide-(25–35)-induced amnesia in the rat , 1997 .

[127]  R. Anwyl,et al.  7-Nitro indazole, a selective neuronal nitric oxide synthase inhibitor in vivo, impairs spatial learning in the rat. , 1996, Learning & memory.

[128]  M. Mattson,et al.  NT-3 and BDNF protect CNS neurons against metabolic/excitotoxic insults , 1994, Brain Research.

[129]  M. Albert,et al.  Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. , 1989, JAMA.

[130]  R. Wurtman,et al.  Metabotropic Glutamate Receptors Increase Amyloid Precursor Protein Processing in Astrocytes: Inhibition by Cyclic AMP , 1997, Journal of neurochemistry.

[131]  R. Beninger,et al.  Excitotoxic action of NMDA agonists on nigrostriatal dopaminergic neurons: modulation by inhibition of nitric oxide synthesis , 1995, Brain Research.

[132]  K. Brunden,et al.  Deposits of Aβ fibrils are not toxic to cortical and hippocampal neurons in vitro , 1996, Neurobiology of Aging.

[133]  R. Wurtman,et al.  Metabotropic glutamate receptor agonists increase release of soluble amyloid precursor protein derivatives from rat brain cortical and hippocampal slices. , 1997, The Journal of pharmacology and experimental therapeutics.

[134]  L. Mucke,et al.  Amyloid precursor proteins protect neurons of transgenic mice against acute and chronic excitotoxic injuries in vivo , 1997, Neuroscience.