Alzheimer's disease

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.

Human Diseases; Neurodegenerative diseases

PMID:15232608

Dickson DW

Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect?

J Clin Invest 114:23-7 (2004)

PMID:15750290

Takuma K, Yan SS, Stern DM, Yamada K

Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer's disease.

J Pharmacol Sci 97:312-6 (2005)

PMID:18675468

Bezprozvanny I, Mattson MP

Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease.

Trends Neurosci 31:454-63 (2008)

PMID:9848086

Holscher C

Possible causes of Alzheimer's disease: amyloid fragments, free radicals, and calcium homeostasis.

Neurobiol Dis 5:129-41 (1998)

PMID:18035450

Bojarski L, Herms J, Kuznicki J

Calcium dysregulation in Alzheimer's disease.

Neurochem Int 52:621-33 (2008)

PMID:15363492

Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M

Induction of neuronal death by ER stress in Alzheimer's disease.

J Chem Neuroanat 28:67-78 (2004)

PMID:11484003

Small DH, Mok SS, Bornstein JC

Alzheimer's disease and Abeta toxicity: from top to bottom.

Nat Rev Neurosci 2:595-8 (2001)

PMID:15295589

Mattson MP

Pathways towards and away from Alzheimer's disease.

Nature 430:631-9 (2004)

PMID:15177383

Parihar MS, Hemnani T

Alzheimer's disease pathogenesis and therapeutic interventions.

J Clin Neurosci 11:456-67 (2004)

PMID:17568632

Cowburn RF, Popescu BO, Ankarcrona M, Dehvari N, Cedazo-Minguez A

Presenilin-mediated signal transduction.

Physiol Behav 92:93-7 (2007)

PMID:17055782

Shen Y, He P, Zhong Z, McAllister C, Lindholm K

Distinct destructive signal pathways of neuronal death in Alzheimer's disease.

Trends Mol Med 12:574-9 (2006)

PMID:18782350

Reese LC, Zhang W, Dineley KT, Kayed R, Taglialatela G

Selective induction of calcineurin activity and signaling by oligomeric amyloid beta.

Aging Cell 7:824-35 (2008)

PMID:10830966

Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH

Neurotoxicity induces cleavage of p35 to p25 by calpain.

Nature 405:360-4 (2000)

PMID:16677790

Hauptmann S, Keil U, Scherping I, Bonert A, Eckert A, Muller WE

Mitochondrial dysfunction in sporadic and genetic Alzheimer's disease.

Exp Gerontol 41:668-73 (2006)

PMID:16529745

Avila J

Tau phosphorylation and aggregation in Alzheimer's disease pathology.

FEBS Lett 580:2922-7 (2006)

PMID:10527810

Ivins KJ, Thornton PL, Rohn TT, Cotman CW

Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8.

Neurobiol Dis 6:440-9 (1999)

PMID:15864339

Gandy S

The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease.

J Clin Invest 115:1121-9 (2005)