Neurotrophin Protection in HIV and Aging

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The introduction of antiretroviral therapies that suppress the systemic HIV burden has greatly extended the life span of infected individuals. However, because these compounds have poor penetration into the central nervous system (CNS), a persistent, active viral reservoir remains that supports the gradual progression and increasing prevalence of CNS disease. As the HIV- infected population ages, chronic inflammation is expected to interact adversely with a variety of age-related disease processes that give rise to cognitive and psychiatric disorders. Our ability to predict and prevent adverse interactions is currently limited by an incomplete understanding of how chronic HIV-associated immune activation causes neurotoxicity and how it might synergize with other diseases. Dendritic beading, pruning and synapse loss are common pathological features of HIV infection, aging and Alzheimer disease. Evidence supports an association between this damage and a loss of neurotrophic support as well as a calcium- dependent disruption of actin regulation and intracellular transport. In independent studies of HIV neuropathogenesis and aging we have demonstrated that the novel p75 neurotrophin ligand, LM11A-31, prevents neural dysfunction and damage, in part, by restoring calcium homeostasis. Recent studies of early Alzheimer pathogenesis suggest that alteration in neurotrophin signaling through the p75 neurotrophin receptor may underlie the development of pathology. Based on these observations, we hypothesize that neurotrophin and calcium signaling converge on mechanisms common to HIV and Alzheimer pathogenesis that regulate the actin cytoskeleton and microtubule-associated proteins. The proposed studies will use in vitro and in vivo models of HIV-associated neuropathogenesis in combination with natural neurotrophins (NGF, proNGF), pathogenic molecules associated with aging (Abeta oligomers) and LM11A-31 to define both deleterious and neuroprotective interactions. Immunostaining and western blot analyses of changes in actin polymerization, tau phosphorylation, microtubule associated protein phosphorylation and functional assessments of mitochondrial transport will be used to determine how each challenge contributes to the development of pathology and/or protection. Normal aging in gp120 transgenic mice will be examined to determine the impact of chronic inflammation model on natural aging using standard measures of cholinergic degeneration as well as more global assessments of microtubule-associated proteins and synapses. The contribution of the p75 neurotrophin receptor to pathogenesis will be evaluated in p75 Exon III knockout mice. The efficacy of treatment with LM11A-31 will then be tested in the aging gp120 mice at a time coincident with the most active development of pathology. These studies will provide insights into the cellular dysfunction associated with age- and HIV- associated loss of neurotrophin support and will determine the therapeutic potential of the novel p75 ligand, LM11A-31.