KEGG   PATHWAY: map05010
Entry
map05010                    Pathway                                

Name
Alzheimer disease
Description
Alzheimer disease (AD) is a chronic disorder that slowly destroys neurons and causes serious cognitive disability. AD is associated with senile plaques and neurofibrillary tangles (NFTs). Amyloid-beta (Abeta), a major component of senile plaques, has various pathological effects on cell and organelle function. To date genetic studies have revealed four genes that may be linked to autosomal dominant or familial early onset AD (FAD). These four genes include: amyloid precursor protein (APP), presenilin 1 (PS1), presenilin 2 (PS2) and apolipoprotein E (ApoE). All mutations associated with APP and PS proteins can lead to an increase in the production of Abeta peptides, specfically the more amyloidogenic form, Abeta42. It was proposed that Abeta form Ca2+ permeable pores and bind to and modulate multiple synaptic proteins, including NMDAR, mGluR5 and VGCC, leading to the overfilling of neurons with calcium ions. Consequently, cellular Ca2+ disruptions will lead to neuronal apoptosis, autophagy deficits, mitochondrial abnormality, defective neurotransmission, impaired synaptic plasticity and neurodegeneration in AD. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.
Class
Human Diseases; Neurodegenerative disease
Pathway map
map05010  Alzheimer disease
map05010

Disease
H00056  Alzheimer disease
Reference
  Authors
Dickson DW
  Title
Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect?
  Journal
J Clin Invest 114:23-7 (2004)
DOI:10.1172/JCI22317
Reference
  Authors
Takuma K, Yan SS, Stern DM, Yamada K
  Title
Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease.
  Journal
J Pharmacol Sci 97:312-6 (2005)
DOI:10.1254/jphs.CPJ04006X
Reference
  Authors
Bezprozvanny I, Mattson MP
  Title
Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease.
  Journal
Trends Neurosci 31:454-63 (2008)
DOI:10.1016/j.tins.2008.06.005
Reference
PMID:9848086
  Authors
Holscher C
  Title
Possible causes of Alzheimer's disease: amyloid fragments, free radicals, and calcium homeostasis.
  Journal
Neurobiol Dis 5:129-41 (1998)
DOI:10.1006/nbdi.1998.0193
Reference
  Authors
Bojarski L, Herms J, Kuznicki J
  Title
Calcium dysregulation in Alzheimer's disease.
  Journal
Neurochem Int 52:621-33 (2008)
DOI:10.1016/j.neuint.2007.10.002
Reference
  Authors
Kondratskyi A, Kondratska K, Skryma R, Prevarskaya N
  Title
Ion channels in the regulation of apoptosis.
  Journal
Biochim Biophys Acta 1848:2532-46 (2015)
DOI:10.1016/j.bbamem.2014.10.030
Reference
  Authors
Popugaeva E, Pchitskaya E, Bezprozvanny I
  Title
Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease.
  Journal
Antioxid Redox Signal 29:1176-1188 (2018)
DOI:10.1089/ars.2018.7506
Reference
  Authors
Tan Y, Deng Y, Qing H
  Title
Calcium channel blockers and Alzheimer's disease.
  Journal
Neural Regen Res 7:137-40 (2012)
DOI:10.3969/j.issn.1673-5374.2012.02.010
Reference
  Authors
Small DH, Mok SS, Bornstein JC
  Title
Alzheimer's disease and Abeta toxicity: from top to bottom.
  Journal
Nat Rev Neurosci 2:595-8 (2001)
DOI:10.1038/35086072
Reference
  Authors
Parihar MS, Hemnani T
  Title
Alzheimer's disease pathogenesis and therapeutic interventions.
  Journal
J Clin Neurosci 11:456-67 (2004)
DOI:10.1016/j.jocn.2003.12.007
Reference
  Authors
Cowburn RF, Popescu BO, Ankarcrona M, Dehvari N, Cedazo-Minguez A
  Title
Presenilin-mediated signal transduction.
  Journal
Physiol Behav 92:93-7 (2007)
DOI:10.1016/j.physbeh.2007.05.053
Reference
  Authors
Honarnejad K, Herms J
  Title
Presenilins: role in calcium homeostasis.
  Journal
Int J Biochem Cell Biol 44:1983-6 (2012)
DOI:10.1016/j.biocel.2012.07.019
Reference
  Authors
Supnet C, Bezprozvanny I
  Title
Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis.
  Journal
Cell Calcium 50:303-9 (2011)
DOI:10.1016/j.ceca.2011.05.013
Reference
  Authors
Hauptmann S, Keil U, Scherping I, Bonert A, Eckert A, Muller WE
  Title
Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease.
  Journal
Exp Gerontol 41:668-73 (2006)
DOI:10.1016/j.exger.2006.03.012
Reference
  Authors
Chen Y, Liu W, McPhie DL, Hassinger L, Neve RL
  Title
APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain.
  Journal
J Cell Biol 163:27-33 (2003)
DOI:10.1083/jcb.200304003
Reference
  Authors
Eckert A, Nisbet R, Grimm A, Gotz J
  Title
March separate, strike together--role of phosphorylated TAU in mitochondrial dysfunction in Alzheimer's disease.
  Journal
Biochim Biophys Acta 1842:1258-66 (2014)
DOI:10.1016/j.bbadis.2013.08.013
Reference
  Authors
Strickland MR, Holtzman DM
  Title
Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1.
  Journal
J Clin Invest 129:969-971 (2019)
DOI:10.1172/JCI127578
Reference
  Authors
Ivins KJ, Thornton PL, Rohn TT, Cotman CW
  Title
Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8.
  Journal
Neurobiol Dis 6:440-9 (1999)
DOI:10.1006/nbdi.1999.0268
Reference
  Authors
Sushma, Mondal AC
  Title
Role of GPCR signaling and calcium dysregulation in Alzheimer's disease.
  Journal
Mol Cell Neurosci 101:103414 (2019)
DOI:10.1016/j.mcn.2019.103414
Reference
  Authors
Sanz-Blasco S, Valero RA, Rodriguez-Crespo I, Villalobos C, Nunez L
  Title
Mitochondrial Ca2+ overload underlies Abeta oligomers neurotoxicity providing an unexpected mechanism of neuroprotection by NSAIDs.
  Journal
PLoS One 3:e2718 (2008)
DOI:10.1371/journal.pone.0002718
Reference
  Authors
Mattson MP
  Title
ER calcium and Alzheimer's disease: in a state of flux.
  Journal
Sci Signal 3:pe10 (2010)
DOI:10.1126/scisignal.3114pe10
Reference
  Authors
Lee SY, Hwang DY, Kim YK, Lee JW, Shin IC, Oh KW, Lee MK, Lim JS, Yoon DY, Hwang SJ, Hong JT
  Title
PS2 mutation increases neuronal cell vulnerability to neurotoxicants through activation of caspase-3 by enhancing of ryanodine receptor-mediated calcium release.
  Journal
FASEB J 20:151-3 (2006)
DOI:10.1096/fj.05-4017fje;1
Reference
  Authors
Katayama T, Imaizumi K, Honda A, Yoneda T, Kudo T, Takeda M, Mori K, Rozmahel R, Fraser P, George-Hyslop PS, Tohyama M
  Title
Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer's disease-linked presenilin-1 mutations.
  Journal
J Biol Chem 276:43446-54 (2001)
DOI:10.1074/jbc.M104096200
Reference
  Authors
Lane-Donovan C, Herz J
  Title
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease.
  Journal
Trends Endocrinol Metab 28:273-284 (2017)
DOI:10.1016/j.tem.2016.12.001
Reference
  Authors
Wasser CR, Herz J
  Title
Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses.
  Journal
J Biol Chem 292:1330-1338 (2017)
DOI:10.1074/jbc.R116.766782
Reference
  Authors
Lilja AM, Porras O, Storelli E, Nordberg A, Marutle A
  Title
Functional interactions of fibrillar and oligomeric amyloid-beta with alpha7 nicotinic receptors in Alzheimer's disease.
  Journal
J Alzheimers Dis 23:335-47 (2011)
DOI:10.3233/JAD-2010-101242
Reference
  Authors
Anastasio TJ
  Title
Computational identification of potential multitarget treatments for ameliorating the adverse effects of amyloid-beta on synaptic plasticity.
  Journal
Front Pharmacol 5:85 (2014)
DOI:10.3389/fphar.2014.00085
Reference
  Authors
Vargas LM, Cerpa W, Munoz FJ, Zanlungo S, Alvarez AR
  Title
Amyloid-beta oligomers synaptotoxicity: The emerging role of EphA4/c-Abl signaling in Alzheimer's disease.
  Journal
Biochim Biophys Acta Mol Basis Dis 1864:1148-1159 (2018)
DOI:10.1016/j.bbadis.2018.01.023
Reference
  Authors
Tu S, Okamoto S, Lipton SA, Xu H
  Title
Oligomeric Abeta-induced synaptic dysfunction in Alzheimer's disease.
  Journal
Mol Neurodegener 9:48 (2014)
DOI:10.1186/1750-1326-9-48
Reference
  Authors
Palomer E, Buechler J, Salinas PC
  Title
Wnt Signaling Deregulation in the Aging and Alzheimer's Brain.
  Journal
Front Cell Neurosci 13:227 (2019)
DOI:10.3389/fncel.2019.00227
Reference
  Authors
Vallee A, Lecarpentier Y
  Title
Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma.
  Journal
Front Neurosci 10:459 (2016)
DOI:10.3389/fnins.2016.00459
Reference
  Authors
Origlia N, Arancio O, Domenici L, Yan SS
  Title
MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE.
  Journal
Expert Rev Neurother 9:1635-45 (2009)
DOI:10.1586/ern.09.107
Reference
  Authors
Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Munch G
  Title
Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease.
  Journal
Neurobiol Aging 32:763-77 (2011)
DOI:10.1016/j.neurobiolaging.2009.04.016
Reference
  Authors
Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J
  Title
Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport.
  Journal
J Neurosci 23:4499-508 (2003)
DOI:10.1523/JNEUROSCI.23-11-04499.2003
Reference
  Authors
Roy S, Zhang B, Lee VM, Trojanowski JQ
  Title
Axonal transport defects: a common theme in neurodegenerative diseases.
  Journal
Acta Neuropathol 109:5-13 (2005)
DOI:10.1007/s00401-004-0952-x
Reference
  Authors
Ferreira ST, Lourenco MV, Oliveira MM, De Felice FG
  Title
Soluble amyloid-beta oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease.
  Journal
Front Cell Neurosci 9:191 (2015)
DOI:10.3389/fncel.2015.00191
Reference
  Authors
De Felice FG, Lourenco MV, Ferreira ST
  Title
How does brain insulin resistance develop in Alzheimer's disease?
  Journal
Alzheimers Dement 10:S26-32 (2014)
DOI:10.1016/j.jalz.2013.12.004
Reference
  Authors
Bedse G, Di Domenico F, Serviddio G, Cassano T
  Title
Aberrant insulin signaling in Alzheimer's disease: current knowledge.
  Journal
Front Neurosci 9:204 (2015)
DOI:10.3389/fnins.2015.00204
Reference
  Authors
Funderburk SF, Marcellino BK, Yue Z
  Title
Cell "self-eating" (autophagy) mechanism in Alzheimer's disease.
  Journal
Mt Sinai J Med 77:59-68 (2010)
DOI:10.1002/msj.20161
Related
pathway
map00190  Oxidative phosphorylation
map03050  Proteasome
map04020  Calcium signaling pathway
map04140  Autophagy - animal
map04141  Protein processing in endoplasmic reticulum
map04210  Apoptosis
map04310  Wnt signaling pathway
map04910  Insulin signaling pathway
map04933  AGE-RAGE signaling pathway in diabetic complications
KO pathway
ko05010   

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