Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia. While cognitive deficits remain the major manifestation of AD, metabolic and non-cognitive abnormalities, such as alterations in food intake, body weight and energy balance are also present, both in AD patients and animal models. In this sense, the tauroursodeoxycholic acid (TUDCA) has shown beneficial effects both in reducing the central and cognitive markers of AD, as well as in attenuating the metabolic disorders associated with it. We previously demonstrated that TUDCA improves glucose homeostasis and decreases the main AD neuromarkers in the streptozotocin-induced AD mouse model (Stz). Besides that, TUDCA-treated Stz mice showed lower body weight and adiposity. Here, we investigated the actions of TUDCA involved in the regulation of body weight and adiposity in Stz mice, since the effects of TUDCA in hypothalamic appetite control and energy homeostasis have not yet been explored in an AD mice model. The TUDCA-treated mice (Stz + TUDCA) displayed lower food intake, higher energy expenditure (EE) and respiratory quotient. In addition, we observed in the hypothalamus of the Stz + TUDCA mice reduced fluorescence and gene expression of inflammatory markers, as well as normalization of the orexigenic neuropeptides AgRP and NPY expression. Moreover, leptin-induced p-JAK2 and p-STAT3 signaling in the hypothalamus of Stz + TUDCA mice was improved, accompanied by reduced acute food intake after leptin stimulation. Taken together, we demonstrate that TUDCA treatment restores energy metabolism in Stz mice, a phenomenon that is associated with reduced food intake, increased EE and improved hypothalamic leptin signaling. These findings suggest treatment with TUDCA as a promising therapeutic intervention for the control of energy homeostasis in AD individuals.
Highlights
Alzheimer’s disease (AD) is a complex neurodegenerative process and the most common cause of dementia in the elderly, causing major progressive deficits in memory and cognitive function[1]
Mice treated with tauroursodeoxycholic acid (TUDCA) present lower body weight and fat pads depots, compared with streptozotocininduced AD mouse model (Stz) mice
Stz + TUDCA mice showed lower body weight, weight gain, and fat accumulation, as well as higher brown adipose tissue (BAT) weight in comparison with those observed in Stz mice (Fig. 1A–D)
Summary
Alzheimer’s disease (AD) is a complex neurodegenerative process and the most common cause of dementia in the elderly, causing major progressive deficits in memory and cognitive function[1]. A substantial body of evidence suggests that metabolic and non-cognitive abnormalities, such as alterations in neuroendocrine functions, body weight, glucose and energy homeostasis, attributable to hypothalamic dysfunction, are an integral part of AD, and may contribute to its p athogenesis[5,6]. Several studies have shown that TUDCA has neuroprotective action in several models of neurodegenerative disorders, including AD and Parkinson’s disease, based on its potent ability to inhibit apoptosis, attenuate oxidative stress, and reduce endoplasmic reticulum (ER) s tress[20]. It is known that TUDCA reduces the accumulation of βA plaques in transgenic APP/PS1 AD mice model, in addition to decreasing the activation of astrocytes and microglia, which results in attenuation of neurotoxic potential and inflammatory response, as well as in decreased loss of neuronal integrity, altogether resulting in improved cognitive ability[21,22,23]
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