Calcium Signaling Deficits in Glia and Autophagic Pathways Contributing to Neurodegenerative Disease.

SIGNIFICANCE: Numerous cellular processes and signaling mechanisms have been identified that contribute to Alzheimer's disease (AD) pathology; however, a comprehensive or unifying pathway that binds together the major disease features remains elusive. As an upstream mechanism, altered calcium (Ca2+) signaling is a common driving force for many pathophysiological events that emerge during normal aging and development of neurodegenerative disease. Recent Advances: Over the previous three decades, accumulated evidence has validated the concept that intracellular Ca2+ dysregulation is centrally involved in AD pathogenesis, including the aggregation of pathogenic ß-amyloid (Aß) and phospho-τ species, synapse loss and dysfunction, cognitive impairment, and neurotoxicity. CRITICAL ISSUES: Although neuronal Ca2+ signaling within the cytosol and endoplasmic reticulum (ER) has been well studied, other critical central nervous system-resident cell types affected by aberrant Ca2+ signaling, such as astrocytes and microglia, have not been considered as thoroughly. In addition, certain intracellular Ca2+-harboring organelles have been well studied, such as the ER and mitochondria; however other critical Ca2+-regulated organelles, such as lysosomes and autophagosomes, have only more recently been investigated. In this review, we examine Ca2+ dysregulation in microglia and astrocytes, as well as key intracellular organelles important for cellular maintenance and protein handling. Ca2+ dysregulation within these non-neuronal cells and organelles is hypothesized to disrupt the effective clearance of misaggregated proteins and cellular signaling pathways needed for memory networks. FUTURE DIRECTIONS: 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.

Integrative transcriptomic meta-analysis of Parkinson's disease and depression identifies NAMPT as a potential blood biomarker for de novo Parkinson's disease.

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.

Voluntary exercise attenuates LPS-induced reductions in neurogenesis and increases microglia expression of a proneurogenic phenotype in aged mice.

BACKGROUND: Microglia 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. METHODS: Adult (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. RESULTS: Data 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. CONCLUSIONS: Collectively, 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.

Diet-induced obesity attenuates endotoxin-induced cognitive deficits.

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. 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.