Age and aging-related comorbidities are among the major risk factors for the development of cognitive disorders. As the population ages, the prevalence and burden of cognitive impairment on public health is expected to increase dramatically. One segment of the aging population that is both rapidly expanding and increasingly vulnerable to cognitive dysfunction is persons with human immunodeficiency virus (HIV)-infection. The central nervous system (CNS) is vulnerable to HIV infection and the incidence of HIV-associated neurocognitive disorder (HAND) significantly increases in older adults. Despite the significance of this clinical problem, surprisingly little basic science research has been done to understand the contribution of aging to the pathogenesis of HAND. Our long-term goal is to understand the fundamental mechanisms of aging that underlie the pathogenesis of neurocognitive disorders in HIV patients. The objective of this proposal is to define the role of senescent neurons in the pathogenesis of HAND. While cellular senescence has historically been associated with proliferating cells, recent evidence from our lab and elsewhere indicates that cell senescence and senescent-associated biomarkers are prevalent in the human brain (both in astrocytes and neurons) of elderly patients. Furthermore, senescent biomarkers are strongly increased in neurons in the brain of patients with AD, FTDL and HIV infection. Our hypothesis is that cell senescence in neurons contributes to the development of HAND. We will test this hypothesis through 3 aims: 1) We will assess the spatial distribution of senescent neurons in the brain of HIV patients of different ages, and with different levels of cognitive impairment. We will examine whether senescent neurons co-localize with other markers of neurodegeneration, such as phospho-tau, and PINCH;2) We will test whether the increased number of senescent neurons in the brain of HIV patients is due to viral components, the presence of senescent astrocytes, and 3) We will investigate the role of mTOR as a likely underlying modulator of neuronal senescence and markers of neurodegeneration. These studies are innovative and relevant because cell senescence in the brain is a recent observation, not yet fully understood, and it is relevant because if our hypothesis is correct, it will point towards possible new treatments for neurocognitive impairment in HIV-infected individuals.
HIV patients are living longer and becoming increasingly susceptible to the diseases of aging in addition to complications of HIV infection such as cognitive dysfunction. Premature aging of neurons or senescence represents a potential area of overlap between HIV-infection in the brain and the most common aging- associated disorder of cognition, Alzheimer's disease. This proposal seeks to characterize the significance of neuronal senescence using cell culture models and postmortem human tissue studies with the long-term goal of identifying novel therapeutic targets for HIV-associated neurocognitive disorders and other aging-related neurological diseases.
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