Altered intracellular signaling and reduced viability of Alzheimer's disease neuronal cybrids is reproduced by β-amyloid peptide acting through receptor for advanced glycation end products (RAGE)

Activation of apoptosis by increased production of amyloid beta peptides (Aβ) has been implicated in neuronal cell death of Alzheimer's disease (AD). We used mitochondrial transgenic cybrid models of sporadic AD (SAD), which overproduce Aβ compared to control (CTL) cybrids, to investigate the effects of endogenously generated Aβ on intracellular signaling pathways and viability. Reducing SAD Aβ production with γ-secretase inhibition altered the total phosphorylation profile of SAD cybrid to one similar to CTL cybrids and enhanced viability to ∼CTL cybrid levels. Treating CTL cybrids with exogenous Aβ or conditioned media (CM) from SAD cybrids activated the signaling pathways active in SAD cybrids under basal condition and decreased viability. Antibodies against receptor for advanced glycation end products (RAGE) blocked Aβ-induced activation of the p38, JNK pathways, and NF-κB in CTL cybrids and offered protection against the neurotoxic effects of Aβ. Expression of SAD mitochondrial genes in cybrids activates stress-related signaling pathways and reduces viability. This SAD phenotype is produced by endogenously generated Aβ and can be replicated by exogenous Aβ acting through RAGE.