title: 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.
abstract: Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.
authors.affiliation: Feil Family Brain and Mind Research Institute and.
authors.forename: Makoto
authors.identifier: http://orcid.org/0000-0003-3397-9908
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Feil Family Brain and Mind Research Institute and.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Feil Family Brain and Mind Research Institute and.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Racchumi
authors.affiliation: Department of Radiology, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Jonathan P
authors.identifier: http://orcid.org/0000-0001-7170-488X
authors.initials: JP
authors.lastname: Dyke
authors.affiliation: Feil Family Brain and Mind Research Institute and coi2001@med.cornell.edu.
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D050154:Adiposity; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000503:physiopathology*; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D004195:Disease Models, Animal; D018450:Disease Progression; D005215:Fasting; D005247:Feeding Behavior; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D007031:Hypothalamus / Q000503:physiopathology*; D020738:Leptin / Q000097:blood / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D058225:Plaque, Amyloid; D015431:Weight Loss / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020738:Leptin; D009478:Neuropeptide Y
keywords: Alzheimer's disease; NPY; amyloid; hypothalamus; leptin