Entry
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
BRITE hierarchy
Pathway map
Ortholog table
Disease
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 NEDD8-activating enzyme E1 regulatory subunit
K04529 amyloid beta A4 precursor protein-binding family B member 1
K00134 glyceraldehyde 3-phosphate dehydrogenase (phosphorylating) [EC:1.2.1.12 ]
K04505 presenilin 1 [EC:3.4.23.-]
K04522 presenilin 2 [EC:3.4.23.-]
K06172 gamma-secretase subunit APH-1
K04380 microtubule-associated protein tau
K03942 NADH dehydrogenase (ubiquinone) flavoprotein 1 [EC:7.1.1.2 ]
K03943 NADH dehydrogenase (ubiquinone) flavoprotein 2 [EC:7.1.1.2 ]
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, acyl-carrier protein
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:7.1.1.2 ]
K03935 NADH dehydrogenase (ubiquinone) Fe-S protein 2 [EC:7.1.1.2 ]
K03936 NADH dehydrogenase (ubiquinone) Fe-S protein 3 [EC:7.1.1.2 ]
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:7.1.1.2 ]
K03941 NADH dehydrogenase (ubiquinone) Fe-S protein 8 [EC:7.1.1.2 ]
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:7.1.1.8 ]
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
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
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
K05862 voltage-dependent anion channel protein 1
K15040 voltage-dependent anion channel protein 2
K15041 voltage-dependent anion channel protein 3
K05863 solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
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
K04726 BH3 interacting domain death agonist
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
K02084 apoptotic protease-activating factor
K04129 muscarinic acetylcholine receptor M1
K04131 muscarinic acetylcholine receptor M3
K04133 muscarinic acetylcholine receptor M5
K04604 metabotropic glutamate receptor 5
K04634 guanine nucleotide-binding protein G(q) subunit alpha
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
K04809 nicotinic acetylcholine receptor alpha-7
K20858 calcium uniporter protein, mitochondrial
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
K09054 cyclic AMP-dependent transcription factor ATF-6 alpha
K09027 X box-binding protein 1
K04452 DNA damage-inducible transcript 3
K08852 serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
K08860 eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1 ]
K04440 mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K03237 translation initiation factor 2 subunit 1
K04374 cyclic AMP-dependent transcription factor ATF-4
K03061 26S proteasome regulatory subunit T1
K03062 26S proteasome regulatory subunit T2
K03063 26S proteasome regulatory subunit T3
K03064 26S proteasome regulatory subunit T4
K03065 26S proteasome regulatory subunit T5
K03066 26S proteasome regulatory subunit T6
K03028 26S proteasome regulatory subunit N1
K03032 26S proteasome regulatory subunit N2
K03033 26S proteasome regulatory subunit N3
K06693 26S proteasome regulatory subunit N4
K03035 26S proteasome regulatory subunit N5
K03036 26S proteasome regulatory subunit N6
K03037 26S proteasome regulatory subunit N7
K03038 26S proteasome regulatory subunit N8
K03039 26S proteasome regulatory subunit N9
K03029 26S proteasome regulatory subunit N10
K03030 26S proteasome regulatory subunit N11
K03031 26S proteasome regulatory subunit N12
K06691 26S proteasome regulatory subunit N13
K10881 26 proteasome complex subunit DSS1
K04741 caspase 12 [EC:3.4.22.-]
K11716 cyclin-dependent kinase 5 activator 1
K14709 solute carrier family 39 (zinc transporter), member 1/2/3
K14710 solute carrier family 39 (zinc transporter), member 4
K14711 solute carrier family 39 (zinc transporter), member 5
K14712 solute carrier family 39 (zinc transporter), member 6
K14713 solute carrier family 39 (zinc transporter), member 7
K14714 solute carrier family 39 (zinc transporter), member 8
K14715 solute carrier family 39 (zinc transporter), member 9
K14716 solute carrier family 39 (zinc transporter), member 10
K14717 solute carrier family 39 (zinc transporter), member 11
K14718 solute carrier family 39 (zinc transporter), member 12
K14719 solute carrier family 39 (zinc transporter), member 13
K14720 solute carrier family 39 (zinc transporter), member 14
K21398 natural resistance-associated macrophage protein 2
K03209 wingless-type MMTV integration site family, member 1
K00182 wingless-type MMTV integration site family, member 2
K00312 wingless-type MMTV integration site family, member 3
K00408 wingless-type MMTV integration site family, member 4
K00444 wingless-type MMTV integration site family, member 5
K00445 wingless-type MMTV integration site family, member 6
K00572 wingless-type MMTV integration site family, member 7
K00714 wingless-type MMTV integration site family, member 8
K01064 wingless-type MMTV integration site family, member 9
K01357 wingless-type MMTV integration site family, member 10
K01384 wingless-type MMTV integration site family, member 11
K01558 wingless-type MMTV integration site family, member 16
K03068 low density lipoprotein receptor-related protein 5/6
K02353 segment polarity protein dishevelled
K03069 frequently rearranged in advanced T-cell lymphomas 1
K03096 frequently rearranged in advanced T-cell lymphomas 2
K03115 casein kinase II subunit beta
K02085 adenomatosis polyposis coli protein
K10396 kinesin family member 5
K19722 receptor for advanced glycosylation end products
K08845 A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04365 B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04366 RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K21421 NADPH oxidase 2 [EC:1.-.-.-]
K21423 NADPH oxidase 4 [EC:1.6.3.-]
K04735 transcription factor p65
K02580 nuclear factor NF-kappa-B p105 subunit
K03156 tumor necrosis factor superfamily, member 2
K05453 macrophage colony-stimulating factor 1
K16195 eukaryotic translation initiation factor 2-alpha kinase 2 [EC:2.7.11.1 ]
K04467 inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K07209 inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07210 inhibitor of nuclear factor kappa-B kinase subunit gamma
K16172 insulin receptor substrate 1
K07187 insulin receptor substrate 2
K17445 insulin receptor substrate 3
K17446 insulin receptor substrate 4
K02649 phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K00922 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K19730 autophagy-related protein 101
K08331 autophagy-related protein 13
K17589 RB1-inducible coiled-coil protein 1
K17985 activating molecule in BECN1-regulated autophagy protein 1
K17889 beclin 1-associated autophagy-related key regulator
K21246 nuclear receptor-binding factor 2
K17906 autophagy-related protein 2
K17908 autophagy-related protein 18
Compound
C01245 D-myo-Inositol 1,4,5-trisphosphate
C04549 1-Phosphatidyl-1D-myo-inositol 3-phosphate
C05981 Phosphatidylinositol-3,4,5-trisphosphate
C16514 Amyloid beta protein 40
C16515 Amyloid beta protein 42
C21011 [Protein]-N(epsilon)-(carboxymethyl)lysine
C21012 [Protein]-N(epsilon)-(carboxyethyl)lysine
Reference
Authors
Dickson DW
Title
Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect?
Journal
Reference
Authors
Takuma K, Yan SS, Stern DM, Yamada K
Title
Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease.
Journal
Reference
Authors
Bezprozvanny I, Mattson MP
Title
Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease.
Journal
Reference
Authors
Holscher C
Title
Possible causes of Alzheimer's disease: amyloid fragments, free radicals, and calcium homeostasis.
Journal
Reference
Authors
Bojarski L, Herms J, Kuznicki J
Title
Calcium dysregulation in Alzheimer's disease.
Journal
Reference
Authors
Kondratskyi A, Kondratska K, Skryma R, Prevarskaya N
Title
Ion channels in the regulation of apoptosis.
Journal
Reference
Authors
Popugaeva E, Pchitskaya E, Bezprozvanny I
Title
Dysregulation of Intracellular Calcium Signaling in Alzheimer's Disease.
Journal
Reference
Authors
Tan Y, Deng Y, Qing H
Title
Calcium channel blockers and Alzheimer's disease.
Journal
Reference
Authors
Small DH, Mok SS, Bornstein JC
Title
Alzheimer's disease and Abeta toxicity: from top to bottom.
Journal
Reference
Authors
Parihar MS, Hemnani T
Title
Alzheimer's disease pathogenesis and therapeutic interventions.
Journal
Reference
Authors
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Title
Presenilin-mediated signal transduction.
Journal
Reference
Authors
Honarnejad K, Herms J
Title
Presenilins: role in calcium homeostasis.
Journal
Reference
Authors
Supnet C, Bezprozvanny I
Title
Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis.
Journal
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
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
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
Reference
Authors
Strickland MR, Holtzman DM
Title
Dr. Jekyll and Mr. Hyde: ApoE explains opposing effects of neuronal LRP1.
Journal
Reference
Authors
Ivins KJ, Thornton PL, Rohn TT, Cotman CW
Title
Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8.
Journal
Reference
Authors
Sushma, Mondal AC
Title
Role of GPCR signaling and calcium dysregulation in Alzheimer's disease.
Journal
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
Reference
Authors
Mattson MP
Title
ER calcium and Alzheimer's disease: in a state of flux.
Journal
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
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
Reference
Authors
Lane-Donovan C, Herz J
Title
ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease.
Journal
Reference
Authors
Wasser CR, Herz J
Title
Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses.
Journal
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
Reference
Authors
Anastasio TJ
Title
Computational identification of potential multitarget treatments for ameliorating the adverse effects of amyloid-beta on synaptic plasticity.
Journal
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
Reference
Authors
Tu S, Okamoto S, Lipton SA, Xu H
Title
Oligomeric Abeta-induced synaptic dysfunction in Alzheimer's disease.
Journal
Reference
Authors
Palomer E, Buechler J, Salinas PC
Title
Wnt Signaling Deregulation in the Aging and Alzheimer's Brain.
Journal
Reference
Authors
Vallee A, Lecarpentier Y
Title
Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma.
Journal
Reference
Authors
Origlia N, Arancio O, Domenici L, Yan SS
Title
MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE.
Journal
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
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
Reference
Authors
Roy S, Zhang B, Lee VM, Trojanowski JQ
Title
Axonal transport defects: a common theme in neurodegenerative diseases.
Journal
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
Reference
Authors
De Felice FG, Lourenco MV, Ferreira ST
Title
How does brain insulin resistance develop in Alzheimer's disease?
Journal
Reference
Authors
Bedse G, Di Domenico F, Serviddio G, Cassano T
Title
Aberrant insulin signaling in Alzheimer's disease: current knowledge.
Journal
Reference
Authors
Funderburk SF, Marcellino BK, Yue Z
Title
Cell "self-eating" (autophagy) mechanism in Alzheimer's disease.
Journal
Related pathway
ko04141 Protein processing in endoplasmic reticulum
ko04933 AGE-RAGE signaling pathway in diabetic complications
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