Increased apoptotic cell death in sporadic and genetic Alzheimer's disease

Eckert, Anne and Marques, Celio A. and Keil, Uta and Schüssel, Katrin and Müller, Walter E.. (2003) Increased apoptotic cell death in sporadic and genetic Alzheimer's disease. Annals of the New York Academy of Sciences, vol. 1010. pp. 604-609.

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Official URL: http://edoc.unibas.ch/dok/A5253478

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Mounting evidence indicates increased susceptibility to cell death and increased oxidative damage as common features in neurons from sporadic Alzheimer's disease (AD) patients but also from familial AD (FAD) cases. Autosomal dominant forms of FAD are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2 (PS1/2). We investigated the effect of the Swedish APP double mutation (APPsw) on oxidative stress-induced cell death mechanisms in PC12 cells. This mutation results in from three- to sixfold increased beta-amyloid (Abeta) production compared with wild-type APP (APPwt). Because APPsw cells secrete low Abeta levels similar to the situation in FAD brains, our cell model represents a very suitable approach to elucidate the AD-specific cell death pathways under more likely physiological conditions. We found that APPsw-bearing cells show decreased mitochondrial membrane potential after exposure to hydrogen peroxide. In addition, activity of the executor caspase 3 after treatment with hydrogen peroxide was elevated in APPsw cells, which seems to be the result of an enhanced activation of both intrinsic and extrinsic apoptosis pathways. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a consequence of an increased vulnerability of neurons by mitochondrial abnormalities resulting in activation of different apoptotic pathways as a consequence to elevated oxidative stress levels. Finally, we propose a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, Abeta production, mitochondrial dysfunction with caspase pathway, and neuronal loss.
Faculties and Departments:03 Faculty of Medicine > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Psychiatrie (Klinik) > Erwachsenenpsychiatrie UPK
UniBasel Contributors:Eckert, Anne
Item Type:Article, refereed
Article Subtype:Research Article
Note:Also published in: Apoptosis: from signaling pathways to therapeutic tools. - New York, N.Y. : New York Academy of Sciences, 2003. - S. 604-609 -- Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:27
Deposited On:22 Mar 2012 13:59

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