Neurotrophic Factor &Cytokine Regulation in Brian Aging

University Of California Irvine, Irvine CA

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Abstract

In the young adult brain, deafferenting lesions and other forms of traumatic insult induce a broad range of responses by microglia (e.g., proliferation, cytokine expression, phagocytosis) which promote growth and recovery but, if unregulated, may contribute to the loss of neuronal integrity and function. Studies during the previous funding period demonstrated that hippocampal deafferentation induces microglial insulin-like growth factor-1 (IGF-1) gene expression in young adults but not in middle-aged or aged rats. IGF-1 is neuroprotective and, in particular, counteracts deleterious effects of pro-inflammatory cytokines and amyloid Abeta. The loss of IGF-1 expression suggests that microglial responses to deafferentation may be broadly impaired with aging and, in particular, that the absence of this protective, anti-inflammatory factor may contribute to increased neuronal vulnerability and exaggerated inflammatory responses beginning to middle age. The proposed research will test this hypothesis in six Specific Aims. Aim 1 will test the hypothesis that microglial responses to deafferentation (cytokine expression, proliferation, phagocytosis) are broadly impaired with age without impairment of temporally associated astroglial trophic responses to deafferentation. Evidence that glucocorticoids inhibit and adrenalectomy disinhibits lesions-induced IGF-1 responses, suggests that glucocorticoids may account for the loss of reactive microglial IGF-1 expression with age; this will be tested in Aim 2. Specific Aim 3 will use the cultured hippocampal slice preparation to test the hypothesis that IGF-1 is directly regulated by the pro-inflammatory cytokine interleukin- 1. Specific Aim 4 will test the hypothesis that the microglial response to deafferentation is typical of inflammatory responses induced by other insults. In particular, studies will test the hypothesis that deafferentation and in vivo Abeta exposure similarly induce microglial IGF-1 expression that is (a) co-regulated by glucocorticoids and (b) los with aging. Aim 5 will test the hypothesis that IGF-1 may protect hippocampal neurons by blocking potentially neurotoxic responses to inflammation associated with amyloid exposure. Specifically the effects of IGF-1 on amyloid- induced nitric oxide, inducible nitric oxide synthase mRNA and TNF mRNA levels will be examined in cultured hippocampal slices. Aim 6 will determine if IGF-1 mRNA and protein are expressed by reactive microglial and astroglial in human brain with and without Alzheimer's Disease. Together the proposed studies will determine if microglial responses to trauma are broadly disturbed during aging, will identify factors underlying the loss of reactive IGF-1 expression with age, and will provide evidence on the degree to which this glial factor can reduce deleterious effects of inflammation and features of aging and Alzheimer's disease.