2026-07-21T14:26:59Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/183512024-11-28T15:36:47Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927

00925njm 22002777a 4500 dc López-Gambero, Antonio J. author Rosell-Valle, Cristina author Medina-Vera, Dina author Navarro, Juan Antonio author Vargas, Antonio author Rivera, Patricia author Sanjuan, Carlos author Rodríguez de Fonseca, Fernando author Suárez, Juan author 2021-05-20 Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development. 10.3390/ijms22105365 1422-0067 1661-6596 International Journal of Molecular Sciences http://hdl.handle.net/10668/4486 34065168 http://hdl.handle.net/20.500.12105/18351 Alzheimer’s disease 5xFAD Insulin signaling Energy expenditure Hypothalamus Neuroinflammation Ghrelin Insulin resistance Leptin Orexin Resistin STAT5 transcription factor Body weight Gastric inhibitory polypeptide Enfermedad de Alzheimer Proteínas sustrato del receptor de insulina Metabolismo energético Hipotálamo Enfermedades neuroinflamatorias Ghrelina Resistencia a la insulina Leptina Orexinas Resistina Factor de transcripción STAT5 Peso corporal Polipéptido inhibidor gástrico A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse