Abstract
There is accumulating evidence from epidemiological studies that changes in body weight are associated with Alzheimer’s disease (AD) from mid-life obesity increasing the risk of developing AD to weight loss occurring at the earliest stages of AD. Therefore, factors that regulate body weight are likely to influence the development and progression of AD. The adipocyte-derived hormone leptin has emerged as a major regulator of body weight mainly by activating hypothalamic neural circuits. Leptin also has several pleotropic effects including regulating cognitive function and having neuroprotective effects, suggesting a potential link between leptin and AD. Here, we will examine the relationship between leptin and AD by reviewing the recent evidence from cellular and animal models to human studies. We present a model where leptin has a bidirectional role in AD. Not only can alterations in leptin levels and function worsen cognitive decline and progression of AD pathology, but AD pathology, in of itself, can disrupt leptin signaling, which together would lead to a downward spiral of progressive neurodegeneration and worsening body weight and systemic metabolic deficits. Collectively, these studies serve as a framework to highlight the importance of understanding the molecular mechanisms underlying the body weight and systemic metabolic deficits in AD, which has the potential to open new avenues that may ultimately lead to novel therapeutic targets and diagnostic tools.
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Acknowledgments
Dr. Anja Kahl provided assistance in translating to English the original 1927 German article by Stief. Mrs. Chihiro Ishii provided original drawings for the figures. The authors gratefully acknowledge research support from the Leon Levy Foundation (MI) and the BrightFocus Foundation (MI). Dr. Makoto Ishii is the recipient of a Paul B. Beeson Award from the National Institute on Aging, the American Federation for Aging Research, The John A. Hartford Foundation and The Atlantic Philanthropies under award K08AG051179. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding agencies.
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McGuire, M.J., Ishii, M. Leptin Dysfunction and Alzheimer’s Disease: Evidence from Cellular, Animal, and Human Studies. Cell Mol Neurobiol 36, 203–217 (2016). https://doi.org/10.1007/s10571-015-0282-7
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DOI: https://doi.org/10.1007/s10571-015-0282-7