Endocrine Regulation of Alcohol Intake

项目摘要/摘要

Project Summary / Abstract Alzheimer's disease is a progressive neurodegenerative brain disease characterized by impairment in cognitive function. Alzheimer's disease is the most common cause of dementia and an estimated 5.8 million people in the United States age 65 and older are living with Alzheimer's dementia in 2020 (alz.org). Accumulation of amyloid beta (Aβ), a misfolded protein, is a key pathological hallmark of Alzheimer's disease but drug candidates targeting Aβ pathways have yielded little success [1]. More recently, changes in metabolism, particularly glucose metabolism, have been identified as a common feature observed in Alzheimer's disease [2, 3]. Notably, approximately 80% of patients with Alzheimer's disease exhibit impairments in glucose tolerance [4]. These observations along with other epidemiological data have led to the postulation that Alzheimer's disease may, in part, be a metabolic disorder [3, 5]. Fibroblast growth factor 21 (FGF21) is an endocrine hormone that corrects metabolic dysfunction and reverses diabetes and obesity in animal models [6]. FGF21 is an important regulator of glucose homeostasis and is a potent insulin sensitizer. Clinical trials with FGF21 mimetics have also demonstrated the efficacy of targeting this pathway to improve metabolic profiles in humans [7]. Interestingly, recent data suggests that FGF21 administration may also prevent neurodegeneration [8-10] and pathological deficits in animal models of Alzheimer's disease [11-13]. While circulating FGF21 levels are derived primarily by the liver [14], our preliminary data reveals the unexpected discovery that FGF21 is also expressed in a very specific region of the central nervous system. Specifically, FGF21 is expressed in the retrosplenial cortex and can signal to the hippocampus and can regulate learning and memory. A previous study demonstrates that FGF21 is induced from neurons in response to mitochondrial stress [9], and we hypothesize that FGF21 induction in this region regulates metabolic processes to prevent neurodegeneration. Several lines of evidence suggest that during prolonged metabolic impairments, endogenous signaling of FGF21 may be impaired leading to a “FGF21 resistant state” [15]. Importantly, administration of pharmacological levels of FGF21 is sufficient to overcome this resistance and restore metabolic homeostasis [16]. In this proposal, we seek to explore whether endogenous FGF21 signaling is also impaired during Alzheimer's disease progression and whether restoration of central FGF21 signaling, via pharmacological administration of FGF21 or local induction of FGF21 via sustained adeno-associated viral delivery, is sufficient to attenuate the cognitive and pathological deficits in a mouse model of Alzheimer's disease. Together, these studies will provide a better understanding of this potential therapeutic approach to treat Alzheimer's Disease and its related dementias.