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Abstract
Autosomal dominant forms of familial Alzheimer's disease (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. Simultaneously, evidence is provided that increased oxidative stress might play a crucial role in the rapid progression of the Swedish FAD. Here we investigated the effect of the Swedish double mutation (K670M/N671L) in the beta-amyloid precursor protein on oxidative stress-induced cell death mechanisms in PC12 cells. Western blot analysis and cleavage studies of caspase substrates revealed an elevated activity of the executor caspase 3 after treatment with hydrogen peroxide in cells containing the Swedish APP mutation. This elevated activity is the result of the enhanced activation of both intrinsic and extrinsic apoptosis pathways, including activation of caspase 2 and caspase 8. Furthermore, we observed an enhanced activation of JNK pathway and an attenuation of apoptosis by SP600125, a JNK inhibitor, through protection of mitochondrial dysfunction and reduction of caspase 9 activity. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress.
Highlights
Autosomal dominant forms of familial Alzheimer’s dis- intramembranous cut of ␥-secretase, which resides in a high ease (FAD) are caused by mutations of the amyloid pre- molecular weight complex composed of presenilin [3], nicastrin cursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2
Our findings provide evidence that the massive neurodegeneration in early age of familial Alzheimer’s disease (FAD) patients could be a result of an increased vulnerability of neurons through activation of different apoptotic pathways as a consequence of elevated levels of oxidative stress
We provide evidence for the enhanced cell death vulnerability caused by the Swedish amyloid precursor protein (APP) mutation and elucidate cell death mechanism probably initiated by intracellularly produced A
Summary
A, amyloid--protein; APP, amyloid precursor protein; AD, Alzheimer’s disease; FAD, familial Alzheimer’s disease; APPsw, Swedish double mutation form of APP; APPwt, wildtype APP; JNK, c-Jun N-terminal kinase; pNA, para-nitroaniline; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; PI, propidium iodide; ANOVA, analysis of variance; CHO, aldehyde. Oxidative stress may cause the activation of c-Jun N-terminal kinase (JNK; known as stress-activated protein kinase) in degenerating neurons in AD [38]. An involvement of JNK pathway by the induction of Fas ligand in A-induced neuronal apoptosis was described by Morishima et al [39]. The inhibition of the JNK pathway was proposed as a potential therapeutic target in AD [41]. We examined the effect of hydrogen peroxide on the activation of different caspases and the JNK pathway to elucidate the relationship between mutant APP expression, increased A production, and neuronal cell death. We investigated the protective effects of caspase inhibitors as well as JNK inhibitor in preventing oxidative stress-mediated cell death
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