In this Issue

Non-invasive detection of neurochemical changes prior to overt pathology in a mouse model of spinocerebellar ataxia type 1

We measured cerebellar neurochemical alterations in a knock-in mouse model of spinocerebellar ataxia type 1, a hereditary movement disorder, using ultra-high field magnetic resonance spectroscopy (MRS). Very early neurochemical alterations were detectable prior to overt pathology in the volume-of-interest for MRS. Alterations were indicative of osmolytic changes and of disturbances in membrane phospholipid and energy metabolism.


Read the Editorial Highlight for this article on page 578 and the full article on page 660.

Presenilin 2 influences miR146 level and activity in microglia

Presenilin 2 (PS2), a membrane associated protease, has been implicated in the pathogenesis of Alzheimer disease. We have previously shown that PS2 plays an important role in curbing the proinflammatory response in microglia. Here, we report the novel finding that PS2 participates in maintaining the basal and cytokine induced expression of the innate immunity regulating microRNA, miR146. These data suggest one mechanism by which PS2 works to reign in proinflammatory microglial behavior and that PS2 dysfunction or deficiency could thus result in unchecked proinflammatory activation contributing to neurodegeneration.


Read the full article on page 592.

Levels of plasma sulfatides C18 : 0 and C24 : 1 correlate with disease status in relapsing–remitting multiple sclerosis

Sulfatides are glycolipids highly enriched in myelin that have been associated with multiple sclerosis (MS). In this study, we have found a positive correlation between levels of specific sulfatides in plasma and increased disability in patients with relapsing-remitting MS. These findings underline the potential use of these molecules as biomarkers for MS.


Read the full article on page 600.

Peptidylglycine α-amidating monooxygenase heterozygosity alters brain copper handling with region specificity

Atp7a, a Cu-transporting P-type ATPase, is localized to the trans-Golgi network and to vesicles distributed throughout the dendritic arbor. Tissue-specific alterations in Atp7a expression were found in mice heterozygous for peptidylglycine α-amidating monooxygenase (PAM), an essential neuropeptide-synthesizing cuproenzyme. Atp7a and PAM are highly expressed in amygdalar interneurons. Reduced amygdalar expression of Atox-1 and Atp7a in PAM heterozygous mice may lead to reduced synaptic Cu levels, contributing to the behavioral and neurochemical alterations seen in these mice.


Read the full article on page 605.

Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca2+ in neurons

We show that activation of mGluR5 with a selective agonist triggers intracellular Ca2+ release in striatal neurons. Released Ca2+ dissociates preformed CaMKIIα from mGluR5 and meanwhile promotes active CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα-sensitive site. This agonist-induced cascade seems to mediate crosstalk between mGluR5 and NMDA receptors in neurons.


Read the full article on page 620.

Activation of α7-containing nicotinic receptors on astrocytes triggers AMPA receptor recruitment to glutamatergic synapses

We find that activation of nicotinic receptors on astrocytes releases a component that specifically recruits AMPA receptors to glutamatergic synapses. The recruitment appears to occur preferentially at what may be ‘silent synapses’, that is, synapses that have all the components required for glutamatergic transmission (including NMDA receptors) but lack sufficient AMPA receptors to generate a response. The results are unexpected and open up new possibilities for mechanisms underlying network formation and synaptic plasticity.


Read the full article on page 632.

Cytochrome c dysregulation induced by HIV infection of astrocytes results in bystander apoptosis of uninfected astrocytes by an IP3 and calcium-dependent mechanism

We demonstrated that HIV infection of astrocytes protects infected cells from apoptosis but results in cell death of surrounding uninfected astrocytes by a mechanism that is dependent on gap junction channels, dysregulation of mitochondrial cytochrome C (CytC), and cell to cell diffusion of inositol trisphosphate (IP3) and calcium. Our data provide essential information about generation of brain reservoirs and the mechanism of toxicity mediated by the virus.


Read the full article on page 644.

Acrolein stimulates the synthesis of IL-6 and C-reactive protein (CRP) in thrombosis model mice and cultured cells

The combined measurements of protein-conjugated acrolein (PC-Acro), IL-6, and C-reactive protein (CRP) in plasma were useful for identifying silent brain infarction. The aim of this study was to determine whether acrolein causes increased production of IL-6 and CRP, and indeed acrolein increased IL-6 synthesis and IL-6 in turn increased CRP synthesis. Furthermore, IL-6 decreased acrolein toxicity in several cell lines.


Read the full article on page 652.

Critical role of Nrf2 in oxidative stress-induced retinal ganglion cell death

This study suggests that NF-E2 related factor 2 (Nrf2), a transcription factor, plays a pivotal role in counteracting oxidative stress. Most importantly, a neuroprotective effect against oxidative stress-induced retinal ganglion cell (RGC) death was achieved with the pharmacological Nrf2 activator CDDO-Im. This suggests that pharmacological treatment to up-regulate Nrf2 signaling may be a new therapeutic technique to protect RGCs.


Read the full article on page 669.

CSF levels of the neuronal injury biomarker visinin-like protein-1 in Alzheimer's disease and dementia with Lewy bodies

Neuronal Ca2+-sensor protein VILIP-1 has been implicated in the calcium-mediated neuronal injury and pathological change of AD. The CSF VILIP-1 and VILIP-1/Aβ1-42 levels had enough diagnostic accuracy to allow the detection and differential diagnosis of AD. CSF VILIP-1 is a useful biomarker for AD. Evaluating the CSF levels of VILIP-1 in AD and DLB patients could facilitate clinical diagnosis.


Read the full article on page 681.

Endothelial nitric oxide deficiency promotes Alzheimer's disease pathology

Cardiovascular risk factors are associated with increased incidence of Alzheimer's disease (AD). A common feature of these risk factors is decreased endothelial nitric oxide (NO). We observed, in mice deficient in endothelial nitric oxide synthase, increased amyloid precursor protein (APP), β-site APP cleaving enzyme 1, amyloid beta levels, microglial activation, and impaired spatial memory. This suggests chronic loss of endothelial NO may be an important contributor to the pathogenesis of sporadic AD.


Read the full article on page 691.

Unfolded protein response to global ischemia following 48 h of reperfusion in the rat brain: the effect of age and meloxicam

In this study, we conclude that the unfolded protein response (UPR) to ischemic/reperfusion insult is age- and probably inflammation-dependent and could play an important role in ischemic vulnerability. The UPR strongly decreased in aged rats, suggesting a reduced ability for cell survival. The increase in the mRNA levels of UPR gene transcripts in 3-month-old animals was abolished or even reverted by treatment with meloxicam, an anti-inflammatory agent.


Read the full article on page 701.

The Parkinson's disease-associated gene PINK1 protects neurons from ischemic damage by decreasing mitochondrial translocation of the fission promoter Drp1

In this study by employing an oxygen–glucose deprivation (OGD) neuronal model, we explored the function of PINK1 in cerebral ischemia. We indicated that PINK1 significantly ameliorated OGD induced cell death and energy disturbance including reduced ATP generation and collapse of mitochondrial membrane potential by attenuating mitochondrial translocation of Drp1, which maintains mitochondrial function and inhibits ischemia-induced mitochondrial fission.


Read the full article on page 711.

Ischemic post-conditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats

Post-conditioning did not attenuate infarction in nude rats measured 2 days post-stroke, but improved neurological function in nude rats and reduced brain damage 30 days after stroke. It resulted in increased-activities of Akt and mTOR, S6K and p-4EBP1. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC.


Read the full article on page 723.

Specific changes of sulfatide levels in individuals with pre-clinical Alzheimer's disease: an early event in disease pathogenesis

To determine lipid changes at the stage of pre-clinical Alzheimer's disease (AD) (i.e., cognitively normal at death, but with AD neuropathology), we performed lipidomics analysis and found that sulfatide levels were significantly lower in subjects with pre-clinical AD compared to those without AD neuropathology. The results suggest that sulfatide loss is among the earliest events of AD development.


Read the full article on page 733.

Alternative polyadenylation and miR-34 family members regulate tau expression

mRNA 3'-untranslated regions (3'-UTR) often regulate transcript stability or translation. Despite the centrality of the tau protein in Alzheimer's and other neurodegenerative diseases, the human tau 3'-UTR has been little studied. This report identifies regions of the tau 3'-UTR that influence expression and shows that microRNA (miR)-34a targets this 3'-UTR to lower expression, which is considered an important therapeutic goal.


Read the full article on page 739.

Genetic variation at the delta-sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs

We propose the following to describe effects of human delta-sarcoglycan (SGCD) variation on sympathetic and cardio-metabolic traits. SGCD variation alters expression, major allele A to minor allele G, augmenting sympathochromaffin norepinephrine (NE) and CHGB release. Increased plasma NE negatively impacts systemic vascular compliance, while mobilizing free fatty acids. Common variation gives rise to phenotypic consequences and without apparent myocardial involvement.


Read the full article on page 750.

Long-term nicotine treatment down-regulates α6β2* nicotinic receptor expression and function in nucleus accumbens

Long-term nicotine treatment decreases dopamine (DA) transmission in the mesolimbic dopaminergic system. Our data suggest this may involve a decrease in α6β2* nicotinic receptor expression and function. These changes may play a key role in nicotine reward and dependence.


Read the full article on page 762.

c-Jun N-terminal kinase regulates mGluR-dependent expression of post-synaptic FMRP target proteins

Expression of many FMRP target proteins is enhanced in FXS. Here, we evaluated the role of JNKs in FXS. We found that JNK signaling is activated upon mGluR stimulation in wild-type neurons. Conversely, JNK activity is basally elevated in fmr1 knockout. Inhibiting JNK reduced the expression of FMRP target proteins and driving JNK activity increased the expression of these proteins.


Read the full article on page 772.

Probenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism

We showed in the present study that probenecid lowers the intra-cellular ATP production by interfering with the cellular metabolism (black and green arrows). We excluded an altered MPP+ uptake via dopamine transporter (DAT) (blue arrow) or a disturbed glycolysis pathway as cause of the potentiated MPP+ toxicity and showed an indirect reduction in the Complex I activity. We therefore hypothesize (red dotted lines) that probenecid acts either by altering substrate oxidation downstream of pyruvate or by influencing the citric acid cycle. We showed that deleterious effects of probenecid can be reversed by extra-cellular ATP (red arrows).


Read the full article on page 782.

Superoxide-dependent uptake of vitamin C in human glioma cells

This study strongly suggests that the Bystander effect, that is, glioma cell interaction with oxidant-producing microglia, could be an important mechanism for glioma vitamin C loading in the absence of functional sodium-vitamin C cotransporter 2 (SVCT2) expression. The high cellular vitamin C load in glioma cells results from a high uptake of extracellular dehydroascorbic acid (DHA) generated by neighboring microglia. This Bystander effect may explain the high antioxidative potential observed in high-grade gliomas, considering that high-grade gliomas may be the only neoplasm where oxidant-producing microglia can almost equal the number of tumor cells.


Read the full article on page 793.

Purine metabolism during neuronal differentiation: the relevance of purine synthesis and recycling

Differentiation of dopaminergic PC6-3 cells is accompanied by increased purine pools and energy state. The lack of a functional purine recycling pathway causes purine limitation in both undifferentiated and differentiated cells, as well as profound loss of dopamine content. The results imply an unknown mechanism by which intracellular purine levels regulate dopamine levels.


Read the full article on page 805.

The notch signaling pathway: its role in focal CNS demyelination and apotransferrin-induced remyelination

Evidence of the participation of Notch signaling in the demyelination/remyelination process will help further understand demyelinating disorders such as Multiple Sclerosis and the use of aTf should be taken into consideration as a possible therapeutic intervention.


Read the full article on page 819.

Dopaminergic neurotoxicity of S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, and S-methyl-N,N-diethylthiocarbamate (MeDETC) in Caenorhabditis elegans

A correlation exists between pesticide use and Parkinson's disease. We investigated the ability of thiocarbamate pesticides to induce dopaminergic neurodegeneration in Caenorhabditis elegans. Treatment with thiocarbamates led to selective loss of dopaminergic cell morphology, and decreased dopamine content and dopaminergic-dependent behavior. Our data suggest that thiocarbamate pesticides may be environmental risk factors for Parkinson's disease.


Read the full article on page 837.

Age-dependent alterations of the kynurenine pathway in the YAC128 mouse model of Huntington disease

We propose that induction of indoleamine 2,3 dioxygenase (Ido1) expression and activity in the striatum by mutant huntingtin (mHTT) plays a central role in the observed imbalance of downstream kynurenine (Kyn) pathway metabolites. This imbalance, and altered transport of kynurenine pathway metabolites through the blood brain barrier (BBB) from blood to CNS, may result in increased sensitivity of striatal neurons to glutamate toxicity in Huntington disease.


Read the full article on page 852.

Retinitis Pigmentosa: over-expression of anti-ageing protein Klotho in degenerating photoreceptors

Retinitis Pigmentosa (RP) involves a hereditary degeneration of photoreceptors. Here, we demonstrate an over-expression of the anti-ageing protein Klotho in several rodent Retinitis Pigmentosa models. The over-expression of the protein is also shown to be linked to the degeneration of photoreceptors. In summary, our work suggests Klotho as a novel player in the retina, with a clear connection to photoreceptor cell death as well as with an influence on retinal organization.


Read the full article on page 868.

Critical role of calpain in spinal cord degeneration in Parkinson's disease

We proposed calpain over-activation and calpain-calpastatin dysregulation driving in a cascade of inflammatory responses (microglial activation and T cell infiltration) and degenerative pathways culminating in axonal degeneration and neuronal death in spinal cord of Parkinson's disease patients. This may be one of the crucial mechanisms in the degenerative process.


Read the full article on page 880.