| First Author | Clarke JR | Year | 2015 |
| Journal | EMBO Mol Med | Volume | 7 |
| Issue | 2 | Pages | 190-210 |
| PubMed ID | 25617315 | Mgi Jnum | J:232678 |
| Mgi Id | MGI:5779786 | Doi | 10.15252/emmm.201404183 |
| Citation | Clarke JR, et al. (2015) Alzheimer-associated Abeta oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Mol Med 7(2):190-210 |
| abstractText | 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 Abeta oligomers (AbetaOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AbetaOs failed to induce glucose intolerance, suggesting AbetaOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AbetaOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2alpha phosphorylation (eIF2alpha-P). AbetaOs further induced eIF2alpha-P and activated pro-inflammatory IKKbeta/NF-kappaB signaling in the hypothalamus of mice and macaques. AbetaOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-alpha (TNF-alpha) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AbetaOs 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 AbetaOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD. |
