ANALYSIS OF ADULT NEUROGENESIS AND HIPPOCAMPUS-DEPENDENT MEMORY IN MOUSE MODELS FOR AGING, ALZHEIMER’S DISEASE AND CRANIAL IRRADIATION-INDUCED NEUROINFLAMMATION
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Aging in the brain is a complex process that affects every living being differently. Age-associated memory decline can be mild; however, memory can deteriorate quickly with in patients with mild cognitive impairment or a significant brain injury. Investigating therapeutics that support learning and memory mechanisms in subjects at risk for cognitive impairment is crucial for aging populations. One therapeutic that has drawn interest in Alzheimer’s disease (AD) research is the diabetic drug, rosiglitazone which specifically binds to the nuclear receptor, peroxisome proliferating activated receptor gamma (PPAR). Inhibition of p38 activity has also been shown to be a viable therapeutic target for conserving cognition in neurodegeneration models. Briefly, the hippocampus is responsible for encoding long-term memories associated with spatial and contextual cognitive tasks and is susceptible to AD pathology. The hippocampus is one of the few areas in the adult brain where new neurons are continuously produced throughout life. Furthermore, hippocampal neurogenesis has been shown to support neighboring neurons and correlate with hippocampal learning and memory performance. However, it is unknown how PPAR and p38 impinge on adult neurogenesis and hippocampal dependent learning and memory in mouse models with risk factors associated with cognitive decline. To empirically answer this question, we chose three models of cognitive decline: aged wild type mice, cranial-irradiated mice and a model of Alzheimer’s disease, Tg2576(APP KM670/671NL Swedish). Here we show attenuating p38 activity improves context fear discrimination and survival of adult-born neurons in aged mice. Similarly, the PPAR agonist RSG rescued cranial irradiated deficits in context discrimination that was independent of adult neurogenesis. In the same model we observed attenuation of Iba-1 expressing microglia in the dorsal hippocampus which has been shown to protect cognition. Lastly, RSG was able to reverse Morris water maze spatial learning and long-term memory but not object recognition or context fear discrimination deficits in the Tg2576 Alzheimer’s mouse model. In conclusion the evidence here supports a role for p38 and PPAR in reversing hippocampal dependent memory deficits.