We are very sad that the ISN lost its President Kazuhiro Ikenaka, Professor and Chairman at National Institute for Physiological Sciences (NIPS), Director of Okazaki Institute of Integrative Biology. JNeurochem published an Obituary to value his outstanding achievements: Akio Wanaka et al. (2019) OBITUARY Kazuhiro Ikenaka (1952‐2018). https://doi.org/10.1111/jnc.14679
The anterior piriform cortex (APC) is activated by, and is the brain area most sensitive to, essential (indispensable) amino acid (IAA) deficiency. The APC is required for the rapid (20 min) behavioral rejection of IAA deficient diets and increased foraging, both crucial adaptive functions supporting IAA homeostasis in omnivores. The biochemical mechanisms signaling IAA deficiency in the APC block initiation of translation in protein synthesis via uncharged tRNA and the general amino acid control kinase, general control nonderepressing kinase 2. Yet, how inhibition of protein synthesis activates the APC is unknown. The neuronal K+Cl? cotransporter, neural potassium chloride co‐transporter (KCC2), and GABAA receptors are essential inhibitory elements in the APC with short plasmalemmal half‐lives that maintain control in this highly excitable circuitry. After a single IAA deficient meal both proteins were reduced (vs. basal diet controls) in western blots of APC (but not neocortex or cerebellum) and in immunohistochemistry of APC. Furthermore, electrophysiological analyses support loss of inhibitory elements such as the GABAA receptor in this model. As the crucial inhibitory function of the GABAA receptor depends on KCC2 and the Cl? transmembrane gradient it establishes, these results suggest that loss of such inhibitory elements contributes to disinhibition of the APC in IAA deficiency.
The formation of neurotoxic prion protein (PrP) oligomers is thought to be a key step in the development of prion diseases. Recently, it was determined that the sonication and shaking of recombinant PrP can convert PrP monomers into β‐state oligomers. Herein, we demonstrate that β‐state oligomeric PrP can be generated through protein misfolding cyclic amplification from recombinant full‐length hamster, human, rabbit, and mutated rabbit PrP, and that these oligomers can be used for subsequent research into the mechanisms of PrP‐induced neurotoxicity. We have characterized protein misfolding cyclic amplification‐induced monomer‐to‐oligomer conversion of PrP from three species using western blotting, circular dichroism, size‐exclusion chromatography, and resistance to proteinase K (PK) digestion. We have further shown that all of the resulting β‐oligomers are toxic to primary mouse cortical neurons independent of the presence of PrPC in the neurons, whereas the corresponding monomeric PrP were not toxic. In addition, we found that this toxicity is the result of oligomer‐induced apoptosis via regulation of Bcl‐2, Bax, and caspase‐3 in both wild‐type and PrP?/? cortical neurons. It is our hope that these results may contribute to our understanding of prion transformation within the brain.
Humanin and calmodulin‐like skin protein (CLSP) inhibits Alzheimer disease (AD)‐related neuronal cell death via the heterotrimeric humanin receptor in vitro . It has been suggested that CLSP is a central agonist of the heterotrimeric humanin receptor in vivo . To investigate the role of CLSP in the AD pathogenesis in vivo , we generated mouse CLSP‐1 transgenic mice, crossed them with the APPswe/PSEN1dE9 mice, a model mouse of AD, and examined the effect of CLSP over‐expression on the pathological phenotype of the AD mouse model. We found that over‐expression of the mouse CLSP‐1 gene attenuated spatial learning impairment, the loss of a presynaptic marker synaptophysin, and the inactivation of STAT3 in the APPswe/PSEN1dE9 mice. On the other hand, CLSP over‐expression did not affect levels of Aβ, soluble Aβ oligomers, or gliosis. These results suggest that the CLSP‐mediated attenuation of memory impairment and synaptic loss occurs in an Aβ‐independent manner. The results of this study may serve as a hint to the better understanding of the AD pathogenesis and the development of AD therapy.
Peptidyl‐prolyl cis/trans isomerases (PPIases), a unique family of molecular chaperones, regulate protein folding at proline residues. These residues are abundant within intrinsically disordered proteins, like the microtubule‐associated protein tau. Tau has been shown to become hyperphosphorylated and accumulate as one of the two main pathological hallmarks in Alzheimer's disease, the other being amyloid beta (Aβ). PPIases, including Pin1, FK506‐binding protein (FKBP) 52, FKBP51, and FKBP12, have been shown to interact with and regulate tau biology. This interaction is particularly important given the numerous proline‐directed phosphorylation sites found on tau and the role phosphorylation has been found to play in pathogenesis. This regulation then affects downstream aggregation and oligomerization of tau. However, many PPIases have yet to be explored for their effects on tau biology, despite the high likelihood of interaction based on proline content. Moreover, Pin1, FKBP12, FKBP52, cyclophilin (Cyp) A, CypB, and CypD have been shown to also regulate Aβ production or the toxicity associated with Aβ pathology. Therefore, PPIases directly and indirectly regulate pathogenic protein multimerization in Alzheimer's disease and represent a family rich in targets for modulating the accumulation and toxicity.
Cocaine is a recreational drug of abuse that binds to the dopamine transporter, preventing reuptake of dopamine into pre‐synaptic terminals. The increased presence of synaptic dopamine results in stimulation of both pre‐ and post‐synaptic dopamine receptors, considered an important mechanism by which cocaine elicits its reinforcing properties. However, the effects of acute cocaine administration on pre‐synaptic dopamine function remain unclear. Non‐invasive imaging techniques such as positron emission tomography have revealed impaired pre‐synaptic dopamine function in chronic cocaine users. Similar impairments have been seen in animal studies, with microdialysis experiments indicating decreased basal dopamine release. Here we use micro positron emission tomography imaging techniques in mice to measure dopamine synthesis capacity and determine the effect of acute cocaine administration of pre‐synaptic dopamine function. We show that a dose of 20 mg/kg cocaine is sufficient to elicit hyperlocomotor activity, peaking 15–20 min post treatment (p < 0.001). However, dopamine synthesis capacity in the striatum was not significantly altered by acute cocaine treatment (: 0.0097 per min vs. 0.0112 per min in vehicle controls, p > 0.05). Furthermore, expression levels of two key enzymes related to dopamine synthesis, tyrosine hydroxylase and aromatic l ‐amino acid decarboxylase, within the striatum of scanned mice were not significantly affected by acute cocaine pre‐treatment (p > 0.05). Our findings suggest that while the regulation of dopamine synthesis and release in the striatum have been shown to change with chronic cocaine use, leading to a reduced basal tone, these adaptations to pre‐synaptic dopaminergic neurons are not initiated following a single exposure to the drug.
The α7 nicotinic receptors (NR) have been confirmed in the heart but their role in cardiac functions has been contradictory. To address these contradictory findings, we analyzed cardiac functions in α7 NR knockout mice (α7−/−) in vivo and ex vivo in isolated hearts. A standard limb leads electrocardiogram was used, and the pressure curves were recorded in vivo, in Arteria carotis and in the left ventricle, or ex vivo, in the left ventricle of the spontaneously beating isolated hearts perfused following Langedorff's method. Experiments were performed under basic conditions, hypercholinergic conditions, and adrenergic stress. The relative expression levels of α and β NR subunits, muscarinic receptors, β1 adrenergic receptors, and acetylcholine life cycle markers were determined using RT-qPCR. Our results revealed a prolonged QT interval in α7−/− mice. All in vivo hemodynamic parameters were preserved under all studied conditions. The only difference in ex vivo heart rate between genotypes was the loss of bradycardia in prolonged incubation of isoproterenol-pretreated hearts with high doses of acetylcholine. In contrast, left ventricular systolic pressure was lower under basal conditions and showed a significantly higher increase during adrenergic stimulation. No changes in mRNA expression were observed. In conclusion, α7 NR has no major effect on heart rate, except when stressed hearts are exposed to a prolonged hypercholinergic state, suggesting a role in acetylcholine spillover control. In the absence of extracardiac regulatory mechanisms, left ventricular systolic impairment is revealed.
People bitten by Alpine vipers are usually treated with antivenom antisera to prevent the noxious consequences caused by the injected venom. However, this treatment suffers from a number of drawbacks and additional therapies are necessary. The venoms of Vipera ammodytes and of Vipera aspis are neurotoxic and cause muscle paralysis by inducing neurodegeneration of motor axon terminals because they contain a presynaptic acting sPLA2 neurotoxin. We have recently found that any type of damage to motor axons is followed by the expression and activation of the intercellular signaling axis consisting of the CXCR4 receptor present on the membrane of the axon stump and of its ligand, the chemokine CXCL12 released by activated terminal Schwann cells. We show here that also V. ammodytes and V. aspis venoms cause the expression of the CXCL12-CXCR4 axis. We also show that a small molecule agonist of CXCR4, dubbed NUCC-390, induces a rapid regeneration of the motor axon terminal with functional recovery of the neuromuscular junction. These findings qualify NUCC-390 as a promising novel therapeutics capable of improving the recovery from the paralysis caused by the snakebite of the two neurotoxic Alpine vipers.
Controversial findings regarding the association between serum cholesterol levels and Alzheimer's disease (AD) have been identified through observational studies. The genetic basis shared by both factors and the causality between them remain largely unknown. The objective of this study is to examine the causal impact of maternal history of AD on changes in serum cholesterol levels in adult offspring. By retrieving genetic variants from summary statistics of large-scale genome-wide association study of maternal history of AD (European-based: Ncase = 27 696, Ncontrol = 260 980). The causal association between genetically predicted maternal history of AD and changes in serum cholesterol levels in adult offspring was examined using the two-sample Mendelian randomization (MR) method. Causal impact estimates were calculated using single-nucleotide polymorphisms in both univariable MR (UMR) and multivariable MR (MVMR) analyses. Additionally, other approaches, such as Cochran's Q test and leave-one-out variant analysis, were employed to correct for potential biases. The results of UMR presented that genetically predicted maternal history of AD was positively associated with hypercholesterolemia (OR = 1.014; 95% CI: 1.009–1.018; p < 0.001), total cholesterol (OR = 1.29; 95% CI: 1.134–1.466; p < 0.001) and low-density lipoprotein (OR = 1.525; 95% CI: 1.272–1.828; p < 0.001) among adult offspring. Genetic predisposition for maternal history of AD to be negatively associated with high-density lipoprotein (OR = 0.889; 95% CI: 0.861–0.917; p < 0.001). The MVMR analysis remained robust and significant after adjusting for diabetes and obesity in offspring. Sufficient evidence was provided in this study to support the putative causal impact of maternal history of AD on the change of serum cholesterol profile in adult offspring. In clinical practice, priority should be given to the detection and monitoring of cholesterol levels in individuals with a maternal history of AD, particularly in the early stages.
This editorial highlights an article by McKee and colleagues in the current issue of Journal of Neurochemistry, in which the authors report epigenetic changes linked to one‐carbon metabolism in prefrontal cortex (PFC) of murine offspring from dams fed high‐fat diet to mimic maternal obesity. The group found that high‐fat diet feeding in utero increases weight gain in offspring and dynamically alters DNA methylation in the PFC of male but not female brains. These epigenetic marks were associated with a shift in brain one‐carbon metabolism (folate and methionine) intermediates and were normalized by early‐life methyl‐donor supplementation in a sex‐specific manner.
Vesicular GABA transporter (VGAT) is expressed in GABAergic and glycinergic neurons, and is responsible for vesicular storage and subsequent exocytosis of these inhibitory amino acids. In this study, we show that VGAT recognizes β‐alanine as a substrate. Proteoliposomes containing purified VGAT transport β‐alanine using Δψ but not ΔpH as a driving force. The Δψ‐driven β‐alanine uptake requires Cl?. VGAT also facilitates Cl? uptake in the presence of β‐alanine. A previously described VGAT mutant (Glu213Ala) that disrupts GABA and glycine transport similarly abrogates β‐alanine uptake. These findings indicated that VGAT transports β‐alanine through a mechanism similar to those for GABA and glycine, and functions as a vesicular β‐alanine transporter.
Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1‐G93A co‐cultures. Deleting TNFR2 from SOD1‐G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1‐G93A/TNFR2?/? mice showed high phospho‐TAR DNA‐binding protein 43 (TDP‐43) accumulation and low levels of acetyl‐tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane‐bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology.
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A virtual issue on Neuroinflammation in nervous system disorders, edited by Tammy Kielian, is now available: http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1471-4159/homepage/virtual_issues.htm#neuroinflammation
Chronically activated microglia contribute to the development of neurodegenerative diseases such as Alzheimer's disease (AD ) by the release of pro‐inflammatory mediators that compromise neuronal function and structure. Modulating microglia functions could be instrumental to interfere with disease pathogenesis. Previous studies have shown anti‐inflammatory effects of acetylcholine (AC h) or norepinephrine (NE ), which mainly activates the β‐receptors on microglial cells. Non‐invasive vagus nerve stimulation (nVNS ) is used in treatment of drug‐resistant depression, which is a risk factor for developing AD . The vagus nerve projects to the brainstem's locus coeruleus from which noradrenergic fibers reach to the Nucleus Basalis of Meynert (NBM ) and widely throughout the brain. Pilot studies showed first signs of cognitive‐enhancing effects of nVNS in AD patients. In this study, the effects of nVNS on mouse microglia cell morphology were analyzed over a period of 280 min by 2‐photon laser scanning in vivo microscopy. Total branch length, average branch order and number of branches, which are commonly used indicators for the microglial activation state were determined and compared between young and old wild‐type and amyloid precursor protein/presenilin‐1 (APP/PS1) transgenic mice. Overall, these experiments show strong morphological changes in microglia, from a neurodestructive to a neuroprotective phenotype, following a brief nVNS in aged animals, especially in APP/PS 1 animals, whereas microglia from young animals were morphologically unaffected.
Parkinson disease (PD) is, without doubt, a burden on modern society as the prevalence increases significantly with age. Owing to this growing number of PD cases, it is more critical than ever to understand the pathogenic mechanisms underlying PD to identify therapeutic targets. The discovery of genetic mutations associated with PD and parkinsonism paves the way toward this goal. Even though, familial forms of the disease represent the minority of PD cases and some forms are so rare that there are only a few affected families, the research on the associated genes is invaluable. Recent additions to PARK mutations are those in PARK15 that encodes the F‐box protein O‐type 7 (FBXO7). In this review, we highlight the recent research on FBXO7, which advances our knowledge of the etiopathological pathways and fills unexpected gaps therein, justifying the dedicated study of rare variants of PD.
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