Alzheimer-associated Ab oligomers impact the central nervous system to induce peripheral metabolic deregulation

Alzheimer’s disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Ab oligomers (AbOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AbOs failed to induce glucose intolerance, suggesting AbOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AbOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2a phosphorylation (eIF2a-P). AbOs further induced eIF2a-P and activated proinflammatory IKKb/NF-jB signaling in the hypothalamus of mice and macaques. AbOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-a (TNF-a) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AbOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AbOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.