BackgroundMicroglia can acquire various phenotypes of activation that mediate their inflammatory and neuroprotective effects. Aging causes microglia to become partially activated towards an inflammatory phenotype. As a result, aged animals display a prolonged neuroinflammatory response following an immune challenge. Currently unknown is whether this persistent neuroinflammation leads to greater reductions in hippocampal neurogenesis. Exercise has been shown to alter microglia activation in aged animals, but the nature of these changes has yet to be fully elucidated. The present study assessed whether aged mice show enhanced reductions in hippocampal neurogenesis following an acute immune challenge with lipopolysaccharide (LPS). Further, we assessed whether voluntary wheel running protects against the effects of LPS.MethodsAdult (4 months) and aged (22 months) male C57BL6/J mice were individually housed with or without a running wheel for a total of 9 weeks. After 5 weeks, mice received a single intraperitoneal LPS or saline injection in combination with four daily injections of bromodeoxyuridine (BrdU) to label dividing cells. Tissue was collected 4 weeks later and immunohistochemistry was conducted to measure new cell survival, new neuron numbers, and microglia activation.ResultsData show that LPS reduced the number of new neurons in aged, but not adult, mice. These LPS-induced reductions in neurogenesis in the aged mice were prevented by wheel running. Further, exercise increased the proportion of microglia co-labeled with brain-derived neurotrophic factor (BDNF) in the aged.ConclusionsCollectively, findings indicate that voluntary wheel running may promote a neuroprotective microglia phenotype and protect against inflammation-induced reductions in hippocampal neurogenesis in the aged brain.

Emerging research indicates that depression could be one of the earliest prodromal symptoms or risk factors associated with the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, but the mechanisms underlying the association between both diseases remains unknown. Understanding the molecular networks linking these diseases could facilitate the discovery of novel diagnostic and therapeutics. Transcriptomic meta-analysis and network analysis of blood microarrays from untreated patients with PD and depression identified genes enriched in pathways related to the immune system, metabolism of lipids, glucose, fatty acids, nicotinamide, lysosome, insulin signaling and type 1 diabetes. Nicotinamide phosphoribosyltransferase (NAMPT), an adipokine that plays a role in lipid and glucose metabolism, was identified as the most significant dysregulated gene. Relative abundance of NAMPT was upregulated in blood of 99 early stage and drug-naïve PD patients compared to 101 healthy controls (HC) nested in the cross-sectional Parkinson’s Progression Markers Initiative (PPMI). Thus, here we demonstrate that shared molecular networks between PD and depression provide an additional source of biologically relevant biomarkers. Evaluation of NAMPT in a larger prospective longitudinal study including samples from other neurodegenerative diseases, and patients at risk of PD is warranted.

Overall, we aim to explore how these disrupted mechanisms could be involved in AD pathology and consider their role as potential therapeutic targets. Antioxid. Redox Signal. 29, 1158-1175.

Normal aging is associated with low-grade neuroinflammation that results from age-related priming of microglial cells. Further, aging alters the response to several anti-inflammatory factors, including interleukin (IL)-4 and IL-13. One intervention that has been shown to modulate microglia activation in the aged brain, both basally and following an immune challenge, is exercise. However, whether engaging in exercise can improve responsiveness to anti-inflammatory cytokines is presently unknown. The current study evaluated whether prior exercise training increases sensitivity to anti-inflammatory cytokines that promote the M2 (alternative) microglia phenotype in adult (5-month-old) and aged (23-month-old) C57BL/6J mice. After 8 weeks of exercise or control housing, mice received bilateral hippocampal injections of an IL-4/IL-13 cocktail or vehicle. Twenty-four hours later hippocampal samples were collected and analyzed for expression of genes associated with the M1 (inflammatory) and M2 microglia phenotypes. Results show that IL-4/IL-13 administration increased expression of the M2-associated genes Fizz1, Ym1, Arginase-1 (Arg1), SOCS1, IL-1ra, and CD206. In response to IL-4/IL-13 administration, aged mice showed increased hippocampal expression of the M2-related genes Arg1, SOCS1, Ym1, and CD206 relative to adult mice. Aged mice also showed increased expression of IL-1β relative to adults, which was unaffected by wheel running or IL-4/IL-13. Wheel running was found to have modest effects on expression of Ym1 and Fizz1 in aged and adult mice. Collectively, our findings indicate that aged mice show a differential response to anti-inflammatory cytokines relative to adult mice and that exercise has limited effects on modulating this response.

Obesity increases susceptibility for numerous diseases and neurological disorders including cardiovascular disease, metabolic syndrome, and dementia. One factor that may contribute to the increased risk for these conditions is the development of chronic inflammation. The current study evaluated whether diet-induced obesity (DIO) affects cognitive performance by increasing neuroinflammation and prolonging the behavioral and inflammatory response to an immune challenge. Adult male C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for 2 or 5 months. After consuming their respective diets for two months, sickness associated behaviors were assessed 4 and 24 hours after a lipopolysaccharide (LPS) or saline injection. In a separate experiment, DIO and control mice were tested for spatial learning in the water maze and challenged with LPS one month later. Peripheral cytokine production was assessed in adipose and spleen samples and the neuroinflammatory response was assessed in hippocampal, cortical, and brain samples. DIO impaired acquisition of a spatial learning task relative to control mice. However, these deficits are unlikely to be related to inflammation as DIO showed no changes in basal cytokine levels within the periphery or brain. Further, in response to LPS DIO mice showed comparable or attenuated levels of the proinflammatory cytokines interleukin-1β and interleukin-6 relative to control mice. DIO also reduced hippocampal expression of brain-derived neurotrophic factor and the pre-synaptic marker synaptophysin. Presently, the data indicate that DIO suppresses aspects of the immune response and that cognitive deficits associated with DIO may be related to reduced neurotrophic support rather than inflammation.

Activation of the immune system can impair cognitive function, particularly on hippocampus dependent tasks. Several factors such as normal aging and prenatal experiences can modify the severity of these cognitive deficits. One additional factor that may modulate the behavioral response to immune activation is obesity. Prior work has shown that obesity alters the activity of the immune system. Whether diet-induced obesity (DIO) influences the cognitive deficits associated with inflammation is currently unknown. The present study explored whether DIO alters the behavioral response to the bacterial endotoxin, lipopolysaccharide (LPS). Female C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for a total of five months. After consuming their respective diets for four months, mice received an LPS or saline injection and were assessed for alterations in spatial learning. One month later, mice received a second injection of LPS or saline and tissue samples were collected to assess the inflammatory response within the periphery and central nervous system (CNS). Results showed that LPS administration impaired spatial learning in the control diet mice, but had no effect in DIO mice. This lack of a cognitive deficit in the DIO female mice is likely due to a blunted inflammatory response within the brain. While cytokine production within the periphery (i.e., plasma, adipose, and spleen) was similar between the DIO and control mice, the DIO mice failed to show an increase in IL-6 and CD74 in the brain following LPS administration. Collectively, these data indicate that DIO can reduce aspects of the neuroinflammatory response as well as blunt the behavioral reaction to an immune challenge.

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