Alzheimer?s disease (AD) is the most common type of age-associated dementia affecting millions of people in the United States, featured with both cognitive decline and memory loss. Although extensive studies have been performed and many mechanisms have been proposed for AD pathology, there are still no interventions that can cure, prevent or even slow AD progression; early diagnosis of the disease is also missing. Among various metabolic and non-cognitive dysfunctions observed in AD patients, body weight loss has long been accepted as a critical clinical manifestation, which occurs even before the onset of cognitive syndromes, worsens along with disease progression, and correlates with increased morbidity, mortality, and amyloid-beta (Ab) aggregation. Similar changes have also been observed in multiple AD transgenic mouse lines, suggesting that body weight loss is a fundamental feature of AD pathology. However, the underlying physiological and pathological mechanisms responsible for the metabolic alterations of AD still remain unknown. Given the recent findings that interventions to improve metabolism could ameliorate cognitive deficits and amyloid pathology in transgenic AD mice, understanding of AD-related body weight loss could have both basic and translational meanings. Here, we hypothesize that body weight loss in AD is caused by increased energy expenditure, given the observations of dysregulated appetite and increased feeding in both AD patients and mouse models (Aim-1). In addition, since amyloid plaques are observed early in the hypothalamus of AD, particularly in the paraventricular nucleus (PVH) region that control energy balances, and both AD patients and mouse models exhibit notably increased GABA levels in the brain with enhanced GABA release around plaques, we further hypothesize that increased GABA production and release exist in the PVH of AD animals (Aim-2). Finally, as demonstrated in the parent grant, we have identified that RIP neurons in the arcuate nucleus (ARC) release GABA, inhibit the PVH neurons that project to the NTS, and prevent HFD-induced obesity by stimulating brown adipose tissue (BAT)-mediated thermogenesis. We then hypothesize that increased GABAergic neurotransmission in the PVH contributes to the elevated energy expenditure and body weight loss in AD (Aim-3). We propose multiple ex vivo and in vivo experiments to assess these hypotheses. Fulfillment of these studies would reveal novel insights into the hypothalamic dysfunctions and weight loss in AD and provide additional targets to treat the disease.
Alzheimer?s disease is an incurable, complex neurodegenerative disease with not only cognitive deficits, but also metabolic and non-cognitive abnormalities, such as body weight loss, neuroendocrine dysfunctions and sleep disorders. The underlying mechanisms are still poorly understood. Here we propose that a hypothalamic neural circuit and increased GABAergic neurotransmission promote energy expenditure and cause body weight loss in AD. We will use mouse genetic approaches to assess this hypothesis.
