Hypoxia activates autophagy and modifies glycolysis and mitochondrial respiration as fundamental cell adaptive mechanisms. This stress is closely related to amyotrophic lateral sclerosis. The recruitment of autophagy and mitochondrial dysfunction are documented in patients and models expressing mutant Cu, Zn superoxide dismutase (SOD1) protein, but their impact in the disease remains unclear. G93ASOD1 cells were more susceptible to hypoxia than wild-type SOD1 cells and showed autophagic stress and inappropriate handling of energy metabolism. Defective adaptation to hypoxia may contribute to neurodegeneration.

We propose that decanoic acid (C10) results in increased mitochondrial number. Our data suggest that this may occur via the activation of the PPARγ receptor and its target genes involved in mitochondrial biogenesis. This finding could be of significant benefit to epilepsy patients who are currently on a strict ketogenic diet. Evidence that C10 on its own can modulate mitochondrial number raises the possibility that a simplified and less stringent C10-based diet could be developed.

We postulated that DJ-1 deficiency may increase microglial neurotoxicity to dopaminergic neurons. We discovered that DJ-1-deficient microglia had increased monoamine oxidase (MAO) activity that resulted in elevation of intracellular reactive oxygen species, nitric oxide, and pro-inflammatory cytokines, leading to increased dopaminergic neurotoxicity. Rasagaline, an MAO inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and neurotoxicity.

The results demonstrate that ethanol or lipopolysaccharide (LPS) triggers toll-like receptor 4 (TLR4) endocytosis by caveolae and clathrin-dependent pathways in astrocytes. We proposed that while clathrin is the protein responsible for TLR4 internalization, caveolin-1/lipid rafts membrane microdomains are required for TLR4 signaling. The results provide new insights into the effects of ethanol on TLR4 signalling in astrocytes, events that may underlie neuroinflammation.

Early neurological deterioration after stroke is not easily predictable. The use of blood biomarkers might help in decision-making processes regarding this complication. By combining a sub-pooling of samples strategy with protein array discovery approach, we have found two new biomarkers: beta-defensin-2 and interleukin-4 receptor. Both biomarkers improve the prediction of poor-outcome over clinical variables in the acute phase of stroke.

We investigated whether complement, a complex of soluble and membrane-associated serum proteins, could pre-synaptically affect the release of classic neurotransmitters in the central nervous system (CNS). Our data provide evidence that complement-induced releasing activity is restricted to glutamatergic nerve endings, where it was accounted for by carrier-mediated release. Our observations add new insights to the knowledge of the molecular events accounting for immune and CNS crosstalk. EAAT = excitatory amino acid transporter.

Formalin-induced nociceptive effect occurs concomitantly with an enhancement of glutamate (Glu) level in the dorsal horn spinal cord. The selective σ1 receptor antagonist S1RA results in inhibition of formalin-evoked Glu release, no modification of GABA levels, and enhancement of noradrenaline (NA) levels. This increased spinal NA activates spinal α2-adrenoceptors producing the attenuation of the formalin-induced pain behaviour

Methamphetamine induces a prolonged plasma corticosterone response in females compared to males. This may be mediated by increased neural activation, involving a greater activation of glucocorticoid receptor-positive cells, in males in the CA3 and cingulate brain regions, which are involved in negative feedback functions. These findings indicate a sex difference in the neural regulation of methamphetamine-induced plasma corticosterone release.

Optic nerves from wild-type and p53-deficient mice, engineered to express cyan fluorescent protein (CFP) in neuronal mitochondria, were subjected to oxygen–glucose deprivation (OGD) in the presence and absence of a specific inhibitor of Class I histone deacetylases. The protective effect of MS-275 was evidenced by mitochondrial preservation, and this was most pronounced in the absence of p53.

Cover Image for this issue: doi: 10.1111/jnc.12555.

Using human APOE2, 3, and 4 isoform-specific transgenic mice, we found a lower brain uptake of docosahexaenoic acid (DHA) in APOE4 than in APOE2 mice that may limit the biodistribution of DHA in cerebral tissues. These data provide a mechanistic explanation for the lack of benefit of DHA in APOE4 carriers on cognitive function and the risk of Alzheimer's disease (AD).

Dysfunctional autophagy is frequently observed in post-mortem brains of patients and animal models of Parkinson's disease. In dopaminergic neurons of the 6-hydroxydopamine (6-OHDA) model, oxidative stress induces Tnfaip8 l1/Oxi-β, which results in increased autophagy by its exclusive binding with FBXW5 to stabilize TSC2. Thus, altered regulation of Tnfaip8 l1/Oxi-β may contribute to dysregulated autophagy in dopaminergic neurons under pathogenic oxidative stress, implicating both Oxi-β and FBXW5 as potential intervention targets for dysfunctional autophagy in dopaminergic neurons under oxidative stress.

Accumulation of mutant huntingtin (mHtt) protein causes Huntington's disease (HD). Sulforaphane (SFN), a naturally occurring compound, increased proteasome and autophagy activities in vivo and enhanced mHtt turnover and cell survival in HD cell models. SFN-mediated mHtt degradation is mainly through the proteasome pathway. These data suggest that SFN can be a therapeutic reagent for treating HD and other intractable disorders.

Properties of dopamine biosynthesis were evaluated in the 6-OHDA model of Parkinson's disease by studying the impact of tyrosine hydroxylase (TH) protein loss on its own phosphorylation and dopamine (DA) tissue content in rat nigrostriatal pathway. A dichotomous response was observed between striatum and substantia nigra in that dopamine per remaining TH decreased in striatum, but increased in substantia nigra. Phosphorylation at ser31 reflected these differences, indicating that ser31 phosphorylation may be critical to maintain dopamine with progressive TH protein loss. Drawings are from slides purchased from Motifolio (http://motifolio.com/).