Alzheimer's disease (AD) is characterized by complex relationships between multiple interrelated biological and pathologic processing. Research efforts have largely focused on aberrantly aggregated oligomeric beta-amyloid (oA?), hyperphosphorylated tau proteins in the brain and more recently, glia-mediated neuroinflammation. Increasing evidence suggests that the peripheral immune system may play a role in the pathogenesis of AD. This is supported by the detection of CD8+ T cells adjacent to plaques inside the brain, as well as a negative association between the number of CD8+ T effector memory cells in the blood of AD subjects and their cognitive function. Moreover, human plasma proteomic assessments have identified the alteration of multiple immunological pathways in AD subjects. The brain is protected by the blood brain barrier (BBB) and communicates with the outside through the choroid plexus, meningeal linings and perivascular spaces. In AD and other neurodegenerative conditions, the BBB integrity is compromised, which may further facilitate the migration of peripheral cells and exchange of immune mediators to the affected brain region. The quality and the quantity of immune responses in the periphery are primarily determined by aging. Both adaptive and innate immunity in the periphery are known to precipitously decline during aging. Peripheral immune dysregulation is also influenced by environment and lifestyle factors, such as psychological stress and metabolic disorders. Both chronic stress and metabolic disorders are known risk factors for AD. In this pilot application, we will investigate the role of peripheral immune dysregulation in the onset and progression of AD in an A? mouse model and to identify the immune components that are involved in the process. Specifically, we will transplant bone marrow from 1) young control mice, 2) old mice, 3) psychologically stressed mice and 4) mice with increased basal inflammation to the young AD mice and we will use neurobehavioral, immunohistological and molecular biology tools to examine AD-associated neuropathology and cognitive function and to assess immunological changes in the periphery, the brain and the BBB. Our study will provide a proof-of-concept as to whether dysregulated peripheral immune system may contribute to the onset and progression of AD-type neuropathology and cognitive dysfunction. Our study will pinpoint the anatomical location and the identities of the peripheral immune components that are involved in the process for future in depth investigations. A successful outcome of the study will also provide impetus to investigate the role of peripheral immunity in other models of neurodegeneration.

Public Health Relevance

Alzheimer's disease (AD) has long been considered a disorder restricted to the brain. Our pilot proposal is a proof-of-concept study to test the hypothesis that dysregulation of peripheral immunity, either during age or by environmental stressors, may contribute to the onset and progression of AD neuropathology and cognitive impairment. A successful outcome of the study will elucidate the role of systemic immunity and identify potential anatomical and cellular components for future in depth investigation.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Mackiewicz, Miroslaw
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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