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    What is the link between obesity / diabetes and Alzheimer's disease?

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    A study from Ralf Jockers team

    Amyloid beta peptide is an endogenous negative modulator of leptin receptor

     

    Alzheimer's disease is characterized by cognitive symptoms like memory loss but also by metabolic dysfunction associated with obesity and diabetes. The study carried out by the team of R. Jockers in collaboration with the teams of V. Prevot (U. Lille), T. Maurice (U. Montpellier) and J. Tavernier (U. Ghent, Belgium) highlights a physical interaction between the amyloid-beta peptide (Aβ), which accumulates in the brains of patients with Alzheimer's disease, and the receptor for leptin (LepR), the hormone that controls hunger and participates in regulation of blood sugar. This binding affects the function of leptin. Preventing the interaction of Aβ with LepR could limit the metabolic and cognitive dysfunctions linked to Alzheimer's disease. This study is published in Neuroendocrinology.

     

    Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide, characterized by progressive memory loss and cognitive dysfunction. At the molecular level, AD is defined by the presence of extracellular aggregates of amyloid-beta (Aβ) peptide, and of intracellular neurofibrillary tangles of tau protein, which correlate to cognitive deficits in advanced AD patients. There is currently no treatment to stop or to revert AD progression and our limited knowledge on the onset of the disease hampers the development of AD-specific drugs. Accumulating evidence suggest that AD involves a metabolic component, with pronounced impairment in brain glucose metabolism and altered response to hormones involved in metabolism. The link between metabolic dysfunction and AD is further supported by the fact that type 2 diabetes (T2D) and mid-life obesity, significantly increase the risk of developing AD.

    Leptin is a hormone primarily produced by adipocytes that regulates food intake and energy metabolism by acting in the hypothalamus. Leptin effects are mediated by its membrane receptor – LepR. The function of the LepR needs to be tightly regulated to maintain glucose and energy homeostasis. Dysfunction on LepR response is associated to metabolic disorders like obesity and T2D.

     

    Here the team directed by Ralf Jockers shows that LepR is directly targeted by Aβ oligomers, which dampens the function of LepR providing a plausible mechanistic explanation for the metabolic dysfunction observed in AD patients. This mechanism can occur early before the first symptoms of AD. Preventing or inhibiting the interaction of Aβ with LepR is expected to improve the responsiveness of the leptin system, with beneficial effects on metabolic regulation and presumably also on cognitive functions. 

     

    Legend: Alzheimer`s disease-related amyloid beta peptide (A𝛃42) binds to leptin receptor and impairs proper leptin signaling.

    Electrophysiological recordings showing that leptin increased the spontaneous firing activity of the POMC neurons in the control (upper panel - Normal) brain slices from mice, but is ineffective in brain slices preincubated with Aß1-42 peptide (bottom panel - Alzheimer).

     

    The authors expect that the Aβ binding assay for LepR developed in this study will assist drug development programs and will contribute to successful therapeutic strategies in the field of AD.

     

    This study was supported by the Association France Alzheimer and the Fondation Philippe Chatrier.

     

    Reference

     

    Amyloid beta peptide is an endogenous negative allosteric modulator of leptin receptor. Cecon E, Lhomme T, Maurice T, Luka M, Chen M, Silva A, Wauman J, Zabeau L, Tavernier J, Prevot V, Dam J, Jockers R. Neuroendocrinology. 2020 Apr 24. doi: 10.1159/000508105. PMID: 32335558

     

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