Transgenic Mice Overexpressing Amyloid Precursor Protein Exhibit Early Metabolic Deficits and a Pathologically Low Leptin State Associated with Hypothalamic Dysfunction in Arcuate Neuropeptide Y Neurons

作者: M. Ishii , G. Wang , G. Racchumi , J. P. Dyke , C. Iadecola

DOI: 10.1523/JNEUROSCI.0872-14.2014

关键词: Cognitive declineHypothalamusLeptin DeficiencyOrexigenicLeptinAmyloid precursor proteinBiologyNeuropeptide Y receptorAmyloidEndocrinologyInternal medicine

摘要: Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While exact pathogenesis AD remains unclear, accumulation amyloid-β (Aβ) derived from amyloid precursor protein (APP) in brain thought to lead neuronal dysfunction death underlying dementia. In this study, we examined whether transgenic mice overexpressing Swedish mutation APP (Tg2576), recapitulating selected features AD, have hypothalamic leptin signaling leading body weight deficits. We found 3-month-old Tg2576 mice, before plaque formation, exhibit decreased with markedly adiposity, low plasma levels, increased energy expenditure without alterations feeding behavior. The expression orexigenic neuropeptide Y (NPY) hypothalamus state was abnormal at basal fasting conditions. addition, arcuate NPY neurons exhibited electrophysiological responses slices or wild-type treated Aβ. Finally, metabolic deficits worsened as aged burden brain. These results indicate excess Aβ can potentially disrupt pathologically process progressively worsens increases. Collectively, these findings suggest an intrinsic pathological identify previously unrecognized pathogenic site action for

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