KEGG   PATHWAY: ko05010Help
Entry
ko05010                     Pathway                                

Name
Alzheimer's disease
Description
Alzheimer's 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. The extracellular Abeta oligomers may activate caspases through activation of cell surface death receptors. Alternatively, intracellular Abeta may contribute to pathology by facilitating tau hyper-phosphorylation, disrupting mitochondria function, and triggering calcium dysfunction. 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. FAD-linked PS1 mutation downregulates the unfolded protein response and leads to vulnerability to ER stress.
Class
Human Diseases; Neurodegenerative diseases
BRITE hierarchy
Pathway map
ko05010  Alzheimer's disease
ko05010

Ortholog table
Disease
H00056  Alzheimer's disease (AD)
Orthology
K06704  disintegrin and metalloproteinase domain-containing protein 10 [EC:3.4.24.81]
K06059  disintegrin and metalloproteinase domain-containing protein 17 [EC:3.4.24.86]
K04520  amyloid beta A4 protein
K04532  amyloid beta precursor protein binding protein 1
K04529  amyloid beta A4 precursor protein-binding family B member 1
K00134  glyceraldehyde 3-phosphate dehydrogenase [EC:1.2.1.12]
K04521  beta-site APP-cleaving enzyme 1 (memapsin 2) [EC:3.4.23.46]
K07747  beta-site APP-cleaving enzyme 2 (memapsin 1) [EC:3.4.23.45]
K20723  reticulon-3
K20720  reticulon-4
K06170  presenilin enhancer 2
K04505  presenilin 1 [EC:3.4.23.-]
K04522  presenilin 2 [EC:3.4.23.-]
K06171  nicastrin
K06172  gamma-secretase subunit APH-1A
K01408  insulysin [EC:3.4.24.56]
K01389  neprilysin [EC:3.4.24.11]
K03942  NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:1.6.99.3 1.6.5.3]
K03943  NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:1.6.99.3 1.6.5.3]
K03944  NADH dehydrogenase (ubiquinone) flavoprotein 3
K03945  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 1
K03946  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 2
K03947  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 3
K03948  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 4
K03949  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 5
K03950  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 6
K03951  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 7
K03952  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 8
K03953  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 9
K03954  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 10
K03955  NADH dehydrogenase (ubiquinone) 1 alpha/beta subcomplex 1
K03956  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 11
K11352  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 12
K11353  NADH dehydrogenase (ubiquinone) 1 alpha subcomplex subunit 13
K03957  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 1
K03958  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 2
K03959  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 3
K03960  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 4
K03961  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 5
K03962  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 6
K03963  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 7
K03964  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8
K03965  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 9
K03966  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 10
K11351  NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 11
K03934  NADH dehydrogenase (ubiquinone) Fe-S protein 1 [EC:1.6.99.3 1.6.5.3]
K03935  NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:1.6.99.3 1.6.5.3]
K03936  NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:1.6.99.3 1.6.5.3]
K03937  NADH dehydrogenase (ubiquinone) Fe-S protein 4
K03938  NADH dehydrogenase (ubiquinone) Fe-S protein 5
K03939  NADH dehydrogenase (ubiquinone) Fe-S protein 6
K03940  NADH dehydrogenase (ubiquinone) Fe-S protein 7 [EC:1.6.99.3 1.6.5.3]
K03941  NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:1.6.99.3 1.6.5.3]
K03967  NADH dehydrogenase (ubiquinone) 1 subunit C1
K03968  NADH dehydrogenase (ubiquinone) 1 subunit C2
K00234  succinate dehydrogenase (ubiquinone) flavoprotein subunit [EC:1.3.5.1]
K00235  succinate dehydrogenase (ubiquinone) iron-sulfur subunit [EC:1.3.5.1]
K00236  succinate dehydrogenase (ubiquinone) cytochrome b560 subunit
K00237  succinate dehydrogenase (ubiquinone) membrane anchor subunit
K00411  ubiquinol-cytochrome c reductase iron-sulfur subunit [EC:1.10.2.2]
K00412  ubiquinol-cytochrome c reductase cytochrome b subunit
K00413  ubiquinol-cytochrome c reductase cytochrome c1 subunit
K00414  ubiquinol-cytochrome c reductase core subunit 1
K00415  ubiquinol-cytochrome c reductase core subunit 2
K00416  ubiquinol-cytochrome c reductase subunit 6
K00417  ubiquinol-cytochrome c reductase subunit 7
K00418  ubiquinol-cytochrome c reductase subunit 8
K00419  ubiquinol-cytochrome c reductase subunit 9
K00420  ubiquinol-cytochrome c reductase subunit 10
K02262  cytochrome c oxidase subunit 3
K02256  cytochrome c oxidase subunit 1 [EC:1.9.3.1]
K02261  cytochrome c oxidase subunit 2
K02263  cytochrome c oxidase subunit 4
K02264  cytochrome c oxidase subunit 5a
K02265  cytochrome c oxidase subunit 5b
K02266  cytochrome c oxidase subunit 6a
K02267  cytochrome c oxidase subunit 6b
K02268  cytochrome c oxidase subunit 6c
K02270  cytochrome c oxidase subunit 7a
K02271  cytochrome c oxidase subunit 7b
K02272  cytochrome c oxidase subunit 7c
K02273  cytochrome c oxidase subunit 8
K02132  F-type H+-transporting ATPase subunit alpha
K02133  F-type H+-transporting ATPase subunit beta [EC:3.6.3.14]
K02136  F-type H+-transporting ATPase subunit gamma
K02134  F-type H+-transporting ATPase subunit delta
K02135  F-type H+-transporting ATPase subunit epsilon
K02126  F-type H+-transporting ATPase subunit a
K02127  F-type H+-transporting ATPase subunit b
K02128  F-type H+-transporting ATPase subunit c
K02138  F-type H+-transporting ATPase subunit d
K02137  F-type H+-transporting ATPase subunit O
K02131  F-type H+-transporting ATPase subunit 6
K02125  F-type H+-transporting ATPase subunit 8
K08683  3-hydroxyacyl-CoA dehydrogenase / 3-hydroxy-2-methylbutyryl-CoA dehydrogenase [EC:1.1.1.178 1.1.1.35]
K01059  lipoprotein lipase [EC:3.1.1.34]
K04524  apolipoprotein E
K04550  low-density lipoprotein receptor-related protein 1 (alpha-2-macroglobulin receptor)
K04390  tumor necrosis factor receptor superfamily member 6
K03158  tumor necrosis factor receptor superfamily member 1A
K02373  FAS-associated death domain protein
K04398  caspase 8 [EC:3.4.22.61]
K04726  BH3 interacting domain death agonist
K02183  calmodulin
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K02158  Bcl-2-antagonist of cell death
K08738  cytochrome c
K02084  apoptotic protease-activating factor
K04399  caspase 9 [EC:3.4.22.62]
K02187  caspase 3 [EC:3.4.22.56]
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K05208  glutamate receptor ionotropic, NMDA 1
K05209  glutamate receptor ionotropic, NMDA 2A
K05210  glutamate receptor ionotropic, NMDA 2B
K05211  glutamate receptor ionotropic, NMDA 2C
K05212  glutamate receptor ionotropic, NMDA 2D
K04850  voltage-dependent calcium channel L type alpha-1C
K04851  voltage-dependent calcium channel L type alpha-1D
K04853  voltage-dependent calcium channel L type alpha-1F
K04857  voltage-dependent calcium channel L type alpha-1S
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04963  ryanodine receptor 3
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K05853  Ca2+ transporting ATPase, sarcoplasmic/endoplasmic reticulum [EC:3.6.3.8]
K09054  cyclic AMP-dependent transcription factor ATF-6 alpha
K08852  serine/threonine-protein kinase/endoribonuclease IRE1 [EC:3.1.26.- 2.7.11.1]
K08860  eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1]
K04741  caspase 12 [EC:3.4.22.-]
K13240  nitric-oxide synthase, brain [EC:1.14.13.39]
K01367  calpain-1 [EC:3.4.22.52]
K03853  calpain-2 [EC:3.4.22.53]
K11716  cyclin-dependent kinase 5 activator 1
K02090  cyclin-dependent kinase 5 [EC:2.7.11.22]
K04380  microtubule-associated protein tau
K03083  glycogen synthase kinase 3 beta [EC:2.7.11.26]
K04397  caspase 7 [EC:3.4.22.60]
K04528  alpha-synuclein
K03156  tumor necrosis factor superfamily, member 2
K04519  interleukin 1 beta
Compound
C00027  Hydrogen peroxide
C00070  Copper
C00076  Calcium cation
C00533  Nitric oxide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C14818  Fe2+
C16845  Peroxynitrite
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
Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M
  Title
Induction of neuronal death by ER stress in Alzheimer's disease.
  Journal
J Chem Neuroanat 28:67-78 (2004)
DOI:10.1016/j.jchemneu.2003.12.004
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
Mattson MP
  Title
Pathways towards and away from Alzheimer's disease.
  Journal
Nature 430:631-9 (2004)
DOI:10.1038/nature02621
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
Shen Y, He P, Zhong Z, McAllister C, Lindholm K
  Title
Distinct destructive signal pathways of neuronal death in Alzheimer's disease.
  Journal
Trends Mol Med 12:574-9 (2006)
DOI:10.1016/j.molmed.2006.10.002
Reference
  Authors
Reese LC, Zhang W, Dineley KT, Kayed R, Taglialatela G
  Title
Selective induction of calcineurin activity and signaling by oligomeric amyloid beta.
  Journal
Aging Cell 7:824-35 (2008)
DOI:10.1111/j.1474-9726.2008.00434.x
Reference
  Authors
Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH
  Title
Neurotoxicity induces cleavage of p35 to p25 by calpain.
  Journal
Nature 405:360-4 (2000)
DOI:10.1038/35012636
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
Avila J
  Title
Tau phosphorylation and aggregation in Alzheimer's disease pathology.
  Journal
FEBS Lett 580:2922-7 (2006)
DOI:10.1016/j.febslet.2006.02.067
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
Gandy S
  Title
The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease.
  Journal
J Clin Invest 115:1121-9 (2005)
DOI:10.1172/JCI25100
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