Amyloid-β Protein Modulates Insulin Signaling in Presynaptic Terminals

Synaptic loss is a major neuropathological correlate of memory decline as a result of Alzheimer's disease (AD). This phenomenon appears to be aggravated by soluble amyloid-beta (A beta) oligomers causing presynaptic terminals to be particularly vulnerable to damage. Furthermore, insulin is known to participate in synaptic plasticity through the activation of the insulin receptor (IR) and the PI3K signaling pathway, while low concentrations of soluble A beta and A beta oligomers aberrantly modulate IR function in cultured neurons. To further examine how A beta and insulin interact in the pathology of AD, the present work analyzes the effect of insulin and A beta in the activation of the IR/PI3K pathway in synaptosomes. We found that insulin increased mitochondrial activity and IR/Akt phosphorylation in synaptosomes taken from both hippocampus and cortex. Also, pretreatment with A beta antagonized insulin's effect on hippocampal synaptosomes, but not vice versa. These results show that A beta can reduce responsiveness to insulin. Combined with evidence that insulin desensitization can increase the risk of developing AD, our results suggest that the initial mechanism that impairs synaptic maintenance in AD might start with A beta changes in insulin sensitivity.