KEGG PATHWAY: map05010

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

Disease

H00056

Alzheimer disease

Reference

PMID:15232608

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

PMID:15750290

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

PMID:18675468

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

PMID:18035450

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

PMID:25450339

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

PMID:29890840

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

PMID:25767489

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

PMID:11484003

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

PMID:15177383

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

PMID:17568632

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

PMID:22842534

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

PMID:21663966

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

PMID:16677790

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

PMID:14557245

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

PMID:24051203

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

PMID:30741722

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

PMID:10527810

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

PMID:31655116

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

PMID:18648507

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

PMID:20332425

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

PMID:16394273

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

PMID:11551913

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

PMID:28057414

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

PMID:27994051

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

PMID:21116052

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

PMID:24847263

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

PMID:29378302

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

PMID:25394486

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

PMID:31191253

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

PMID:27807401

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

PMID:19903023

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

PMID:19464758

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

PMID:12805290

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

PMID:15645263

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

PMID:26074767

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

PMID:24529521

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

PMID:26136647

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

PMID:20101724

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

All links

Chemical substance (19)   
   KEGG COMPOUND (19)   
Gene (678383)   
   KEGG ORTHOLOGY (300)   
   RefGene (678083)   
Literature (39)   
   PubMed (39)   
All databases (678441)   

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