Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent form of dementia in elderly people
We recently demonstrated the former in two different mouse models of AD, namely the 3xTg-AD mice and the Tg2576 mice, by crossing them with GFAP-sgp130Fc mice in order to obtain 3xTg-AD mice with the IL-6 trans-signaling pathway blocked in the central nervous system (CNS) [26]
F&Rand results indicate that animals hadhad lower bodybody weight
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent form of dementia in elderly people It courses with impaired cognitive functions and memory loss caused mainly by the accumulation of β-amyloid peptides (Aβ) forming extracellular plaques and the intracellular aggregation of hyperphosphorylated Tau protein forming neurofibrillary tangles [1]. Some studies using diet-induced obesity rodent models demonstrate impairment in memory and learning [7,8], reduced synaptic plasticity [9] and eventually compromised neurogenesis [10] These effects may be caused by the infiltration of cytokines from the periphery and by local neuroinflammatory processes and subsequent alteration of insulin pathways in the brain [11,12]. An altered insulin signaling in the brain contributes to Aβ aggregation and increases hyperphosphorylated tau protein levels [13]
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