Abstract
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.
Highlights
Physical decline and impairment of metabolic homeostasis are the main features of the human aging process [1]
We aimed to investigate food intake, energy expenditure, and neuroinflammation and the mechanisms regulating these processes in the hypothalami of 6-month-old male and female 5xFAD (FAD: family Alzheimer’s disease) transgenic mouse model of AD, which is one of the most early onset AD models of neurodegeneration and amyloid pathology, where cognitive decline starts by age of 4 months increases through age [15,16,17]
We found that 5xFAD mice had a decreased body weight, which was associated with a decreased food intake rather than changes in energy expenditure, 5xFAD female mice exhibited a decreased energy expenditure and respiratory quotient, suggesting a sex-specific change in lipid oxidation resulting from Aβ overexpression
Summary
Physical decline and impairment of metabolic homeostasis are the main features of the human aging process [1]. Central insulin resistance is a common feature linked to premature aging and observed in neurological disorders, including early stages of Alzheimer’s disease (AD) [2]. AD is a progressive neurological disorder with a mostly sporadic origin that is characterized by the loss of cognitive functions such as memory, reasoning, or language, leading to death at about 3–9 years after diagnosis. Recent studies suggest that unhealthy dietary habits and microbiota changes mediate neuroinflammation, modify neurovascular coupling, and create metabolic disturbances deriving on oxidate/nitrosative stress and insulin resistance. All these factors have been identified to contribute to the cognitive decline in AD patients
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