Abstract
BackgroundA typical pathological feature of Alzheimer's disease (AD) is the appearance in the brain of senile plaques made up of β-amyloid (Aβ) and neurofibrillary tangles. AD is also associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al), plays a relevant role in affecting Aβ aggregation and neurotoxicity.MethodologyIn this study, employing a microarray analysis of 35,129 genes, we investigated the effects induced by the exposure to the Aβ1–42-Al (Aβ-Al) complex on the gene expression profile of the neuronal-like cell line, SH-SY5Y.Principal FindingsThe microarray assay indicated that, compared to Aβ or Al alone, exposure to Aβ-Al complex produced selective changes in gene expression. Some of the genes selectively over or underexpressed are directly related to AD. A further evaluation performed with Ingenuity Pathway analysis revealed that these genes are nodes of networks and pathways that are involved in the modulation of Ca2+ homeostasis as well as in the regulation of glutamatergic transmission and synaptic plasticity.Conclusions and SignificanceAβ-Al appears to be largely involved in the molecular machinery that regulates neuronal as well as synaptic dysfunction and loss. Aβ-Al seems critical in modulating key AD-related pathways such as glutamatergic transmission, Ca2+ homeostasis, oxidative stress, inflammation, and neuronal apoptosis.
Highlights
The abnormal deposition and aggregation of b-amyloid (Ab) in senile plaques are hallmarks features of the Alzheimer’s disease (AD) brain
Senile plaques are made up of aggregates of misfolded Ab that are associated with high concentrations of several endogenous or exogenous metal ions (Fe, Zn, Cu, and Al), but they contain cell elements migrating from the immunoresponse system [1,2]
To gain insights on the global changes in gene expression produced by the exposure to the Ab-Al complex in human SHSY5Y neuroblastoma cells, microarray analysis was performed and results selectively compared with gene expression of cultures exposed to Ab or Al
Summary
The abnormal deposition and aggregation of b-amyloid (Ab) in senile plaques are hallmarks features of the Alzheimer’s disease (AD) brain. Metal ions have been indicated as important co-risk factors in several neurodegenerative disorders [3,4] and, in the context of AD, recent studies have shown that they are key in accelerating Ab oligomerization as well as modifying the neurotoxic properties of the amyloid peptide [5,6,7]. AD is associated with an abnormal accumulation of some metal ions, and we have recently shown that one of these, aluminum (Al), plays a relevant role in affecting Ab aggregation and neurotoxicity
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