Endoplasmic reticulum stress links impaired insulin signaling and Alzheimer's disease

Alzheimer's disease (AD) has been linked to impaired brain insulin signaling. In type 2 diabetes, endoplasmic reticulum (ER) stress plays a key role in triggering peripheral insulin resistance. AD brains also present elevated levels of ER stress markers. Therefore, it is possible that common mechanisms underlie impaired brain insulin signaling in AD and peripheral insulin resistance in diabetes. We investigated whether Aβ oligomers (AβOs), synaptotoxins recently implicated in neuronal insulin resistance, induce ER stress response in hippocampal neurons in vitro and in vivo. Pharmacological approaches were employed to further address the mechanisms by which AβOs exert this toxic effect. Furthermore, next-generation GLP-1 analogues were used to bolster neuroprotective signaling and to possibly promote beneficial effects in different AD models. Here, we found that Aβ oligomers markedly increase neuronal ER stress. Levels of phosphorylated eukaryotic initiation factor 2Î (peIF2Î) and ER membrane-associated inositol-requiring enzyme 1 (pIRE1) were elevated in mature cultured hippocampal neurons exposed to oligomers. Elevated ER stress markers were also verified in hippocampi of APPSwe,PS1deltaE9 AD transgenic mice. Importantly, intracerebroventricular injection of Aβ oligomers triggered ER stress in the hippocampi of adult cynomolgus monkeys. We further found that oligomer-induced phosphorylation of eIF2α is mediated by TNF-α/JNK proinflammatory signaling. Double-stranded RNA-dependent protein kinase (PKR), recently described as a critical component that responds to ER stress in peripheral tissue, was here found to be activated by oligomers in neuronal cultures, as well as in transgenic mice and in monkey brains. Stimulation of insulin signaling by GLP-1 receptor agonists or insulin prevented oligomer-induced neuronal pathologies in vitro. GLP-1 agonists further decreased hippocampal ER stress and improved cognition in transgenic mice. We demonstrate that ER stress in AD is mediated by inflammatory mechanisms and reverted by insulinotropic signaling. Results establish that pathological ER stress in AD is linked to impaired brain insulin signaling and provide insight into the protective mechanisms of anti-diabetic agents in the brain.