Cell-derived soluble oligomers of human amyloid-β peptides disturb cellular homeostasis and induce apoptosis in primary hippocampal neurons

摘要

The concentrations of soluble β-amyloid (Aβ) oligomers paralleled with the extent of synaptic loss and severity of cognitive impairment in Alzheimer patients. However, the neurotoxicity of the naturally generated Aβ species remains unknown. This study was designed to examine the effects of naturally generated Aβ oligomers, secreted from amyloid precursor protein-expressing cells, on the homeostasis and viability of primary hippocampal neurons. Our results showed that primary hippocampal neurons incubated with condition media containing cell-secreted soluble Aβ had higher levels of heat-shock protein (HSP)27, HSP60 and HSP70, and lower levels of HSP32 than those of the control neurons. The cell-secreted soluble Aβ caused mitochondria dysfunction in hippocampal neurons as demonstrated by depolarized membrane potential and decreased cytochrome c oxidase activity and ATP levels. The levels of pro-apoptotic proteins, Bid, Bax and cytochrome C, were elevated; whereas anti-apoptotic Bcl-2 protein was reduced in the soluble Aβ-cultured neurons. Apoptosis was also evident in these soluble Aβ-cultured neurons. These results indicate that naturally secreted Aβ induces neuronal injury/death by activating an apoptotic pathway involving impaired mitochondria function and cellular homeostasis.