The db mutation improves memory in younger mice in a model of Alzheimer's disease |
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Authors: | Le Zhang Sun-Ok Fernandez-Kim Tina L Beckett Dana M Niedowicz Katharina Kohler Kalavathi Dasuri Annadora J Bruce-Keller M Paul Murphy Jeffrey N Keller |
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Institution: | 1. Institute of Gerontology, Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 JieFang Avenue, Wuhan, Hubei 430030, China;2. Institute for Dementia Research and Prevention, Pennington Biomedical Research Center/LSU System, 6400 Perkins Road, Baton Rouge, LA 70808, USA;3. Sanders Brown Center on Aging, University of Kentucky, 800 S. Limestone, Sanders Brown 211, Lexington, KY 40536-0230, USA;4. Department of Molecular and Cellular Biochemistry, University of Kentucky, 800 S. Limestone, Sanders Brown 211, Lexington, KY 40536-0230, USA |
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Abstract: | Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, while obesity is a major global public health problem associated with the metabolic disorder type 2 diabetes mellitus (T2DM). Chronic obesity and T2DM have been identified as invariant risk factors for dementia and late-onset AD, while their impacts on the occurrence and development of AD remain unclear. As shown in our previous study, the diabetic mutation (db, Leprdb/db) induces mixed or vascular dementia in mature to middle-aged APPΔNL/ΔNL x PS1P264L/P264L knock-in mice (db/AD). In the present study, the impacts of the db mutation on young AD mice at 10 weeks of age were evaluated. The db mutation not only conferred young AD mice with severe obesity, impaired glucose regulation and activated mammalian target of rapamycin (mTOR) signaling pathway in the mouse cortex, but lead to a surprising improvement in memory. At this young age, mice also had decreased cerebral Aβ content, which we have not observed at older ages. This was unlikely to be related to altered Aβ synthesis, as both β- and γ-secretase were unchanged. The db mutation also reduced the cortical IL-1β mRNA level and IBA1 protein level in young AD mice, with no significant effect on the activation of microglia and astrocytes. We conclude that the db mutation could transitorily improve the memory of young AD mice, a finding that may be partially explained by the relatively improved glucose homeostasis in the brains of db/AD mice compared to their counterpart AD mice, suggesting that glucose regulation could be a strategy for prevention and treatment of neurodegenerative diseases like AD. |
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Keywords: | Correspondence to: L Zhang Institute of Gerontology Department of Geriatrics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology 1095 JieFang Avenue Wuhan Hubei 430030 China Alzheimer's disease Db mutation Glucose regulation Aβ synthesis Cognitive function |
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