Figure 2.

AβOs trigger brain metabolic stress in Alzheimer’s Disease (AD). Accumulation of AβOs in pre-AD brains instigates an inflammatory response that involves increased TNF-α production. TNF-α, in turn, acts on neurons to promote the activity of stress kinases (e.g., PKR, JNK, IKKα), which will serine phosphorylate both eIF2α-P to attenuate translation, and IRS-1 to impair insulin signaling. The combination of repressed protein synthesis and defective insulin signaling are components of a novel form of neuronal metabolic stress that may contribute to synapse deregulation and cognitive impairment in AD.