Alzheimer‐associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

Abstract

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 Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs 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 AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.

Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

“…In vivo, these results were confirmed in crabgrass macaques and APP/PS1 transgenic mice, which received intracerebroventricular (ICV) injections of Aβ oligomers [162]. Consistently, several rodent models of amyloid pathology develop metabolic alterations such as glucose intolerance [163-166]. Particularly interesting is the observation of impaired glucose homeostasis following ICV injections of Aβ oligomers [162].…”

Neuroendocrine-Metabolic Dysfunction and Sleep Disturbances in Neurodegenerative Disorders: Focus on Alzheimer’s Disease and Melatonin

“…The origin of IR in the AD brain seems to be related to both Aβ and tau pathologies [28]. The intracerebroventricular infusion of Aβ oligomers in mice triggers a pre-diabetic state (impaired glucose tolerance) by a hypothalamic-based mechanism [28], and loss of function of tau impairs insulin responsiveness and is associated with altered glucose homeostasis [29]. This is in line with increased brain insulin receptor substrate-1 (IRS-1) inhibition in patients with pure taupathies [30].…”

Getting a “GRiP” on Hypothalamic Endoplasmic Reticulum Stress to Combat Obesity

“…Interestingly, hypothalamic ER stress was recently described in mouse and nonhuman primate models of Alzheimer disease (22). In mice, glucose intolerance caused by induction of experimental Alzheimer disease features was rescued when central ER stress was reduced by treatment with TUDCA (22).…”

“…In mice, glucose intolerance caused by induction of experimental Alzheimer disease features was rescued when central ER stress was reduced by treatment with TUDCA (22). Alzheimer disease and other degenerative metabolic disorders are commonly associated with the accumulation of misfolded and aggregated proteins, and the identification of chaperones, such as GRP78/BiP, that play a crucial role in ER homeostasis will advance our knowledge on how to control aberrant stress signaling associated with such diseases.…”