Alzheimer's disease - the most common age-related neurodegenerative disorder - is a personal and societal tragedy of immense and growing proportions. Over 5 million Americans currently suffer from Alzheimer's disease (AD), and the number is expected to triple by 2050. Despite recent progress in characterizing AD, therapeutic interventions have been disappointing in large part because we lack a complete understanding of the mechanisms that contribute to this disease. Research suggests that peripheral inflammation is an important and modifiable risk factor for AD, and epidemiologic studies suggest that mid-life metabolic syndrome, obesity, and hypertension are inter-related health care conditions that increase the risk of age-related neurodegenerative disorders, particularly AD. The mechanistic links between these systemic disorders and neurodegeneration are poorly understood, but may be the key to developing effective anti-AD therapeutics. These risk factors are particularly prevalent in African Americans, who are also at increased risk for AD. The novel overarching hypothesis of this proposal is that chronic systemic disorders (i.e. metabolic syndrome and hypertension) are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking across the blood brain barrier (BBB) and leading to chronic neuroinflammation, CNS dysfunction, and cognitive decline. To test this hypothesis, we have assembled an interdisciplinary team of experts in inflammation, RAS dysfunction and neurodegeneration to address the following questions: 1) What is the relationship between chronic peripheral inflammation and Alzheimer-like pathology in a transgenic mouse model of Alzheimer-like pathology? 2) How is overactivation of the renin-angiotensin system related to brain inflammation, immune function and AD-like pathogenesis in this model? and 3) How is RAS dysfunction related to central inflammation and immune function in humans at risk for AD? In addressing the third question we will focus on African Americans, who are particularly vulnerable to metabolic syndrome and AD yet have received little attention in systematic investigations. Successful completion of the proposed studies will provide new and potentially paradigm- shifting mechanistic information on how diet- and hypertension-induced chronic peripheral inflammation and chronic brain inflammation contribute to the development of AD.

Public Health Relevance

Mid-life obesity and hypertension increase the risk of developing Alzheimer's disease (AD) in old age, but the mechanistic links between these systemic disorders and dementia are unknown. Using mouse models of AD and a unique cohort of at-risk humans, the proposed studies will furnish new mechanistic information on how dysfunction of the renin-angiotensin system that controls blood pressure, chronic peripheral inflammation, and brain inflammation contribute to the development of AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Wise, Bradley C
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Emory University
Schools of Medicine
United States
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Tansey, MalĂș G; Romero-Ramos, Marina (2018) Immune system responses in Parkinson's disease: Early and dynamic. Eur J Neurosci :
Houser, Madelyn C; Chang, Jianjun; Factor, Stewart A et al. (2018) Stool Immune Profiles Evince Gastrointestinal Inflammation in Parkinson's Disease. Mov Disord 33:793-804
de Sousa Rodrigues, Maria Elizabeth; Bekhbat, Mandakh; Houser, Madelyn C et al. (2017) Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice. Brain Behav Immun 59:158-172
MacPherson, Kathryn P; Sompol, Pradoldej; Kannarkat, George T et al. (2017) Peripheral administration of the soluble TNF inhibitor XPro1595 modifies brain immune cell profiles, decreases beta-amyloid plaque load, and rescues impaired long-term potentiation in 5xFAD mice. Neurobiol Dis 102:81-95