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Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which is alarming given that obesity prevalence peaks at middle age and obesity rates are accelerating worldwide. Midlife, but not late-life obesity increases AD risk, suggesting that this interaction is specific to preclinical AD. AD pathology begins in middle age, with accumulation of amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, and neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach in young adult (6.5 months old) male and female TgF344-AD rats that overexpress mutant human amyloid precursor protein and presenilin-1 and wild-type (WT) controls to determine whether inducing obesity with a high-fat/high-sugar "Western" diet during preclinical AD increases brain metabolic dysfunction in dorsal hippocampus (dHC), a brain region vulnerable to the effects of obesity and early AD. Analyses of dHC gene expression data showed dysregulated mitochondrial and neurotransmission pathways, and up-regulated genes involved in cholesterol synthesis. Western diet amplified the number of genes that were different between AD and WT rats and added pathways involved in noradrenergic signaling, dysregulated inhibition of cholesterol synthesis, and decreased intracellular lipid transporters. Importantly, the Western diet impaired dHC-dependent spatial working memory in AD but not WT rats, confirming that the dietary intervention accelerated cognitive decline. To examine later consequences of early transcriptional dysregulation, we measured dHC monoamine levels in older (13 months old) AD and WT rats of both sexes after long-term chow or Western diet consumption. Norepinephrine (NE) abundance was significantly decreased in AD rats, NE turnover was increased, and the Western diet attenuated the AD-induced increases in turnover. Collectively, these findings indicate obesity during prodromal AD impairs memory, potentiates AD-induced metabolic decline likely leading to an overproduction of cholesterol, and interferes with compensatory increases in NE transmission., (© 2023 International Society for Neurochemistry.)

Collybistin (CB) is a guanine nucleotide exchange factor (GEF) selectively localized at GABAergic and glycinergic postsynapses. Analysis of mRNA shows that several isoforms of collybistin are expressed in the brain. Some of the isoforms have a SH3 domain (CBSH3+) and some have no SH3 domain (CBSH3-). The CBSH3+ mRNAs are predominantly expressed over CBSH3-. However, in an immunoblot study of mouse brain homogenates, only CBSH3+ protein isoforms were detected, proposing that CBSH3- protein might not be expressed in the brain. The expression or lack of expression of CBSH3- protein is an important issue because CBSH3- has a strong effect in promoting the postsynaptic clustering of gephyrin and GABA-A receptors (GABA A Rs). Moreover CBSH3- is constitutively active; therefore lower expression of CBSH3- protein might play a relatively stronger functional role than the more abundant but self-inhibited CBSH3+ isoforms, which need to be activated. We are now showing that: (a) CBSH3- protein is expressed in the brain; (b) parvalbumin positive (PV+) interneurons show higher expression of CBSH3- protein than other neurons; (c) CBSH3- is associated with GABAergic synapses in various regions of the brain and (d) knocking down CBSH3- in hippocampal neurons decreases the synaptic clustering of gephyrin and GABA A Rs. The results show that CBSH3- protein is expressed in the brain and that it plays a significant role in the size regulation of the GABAergic postsynapse., (© 2020 International Society for Neurochemistry.)

This special issue of the Journal of Neurochemistry, entitled "Cholinergic Mechanisms," presents 15 reviews and two original papers, which have been selected to cover the broad spectrum of topics and disciplines presented at the XVIth International Symposium on Cholinergic Mechanisms (ISCM-XVI), ranging from the molecular and the cellular to the clinical and the cognitive mechanisms of cholinergic transmission. The authors discuss recent developments in the field, for instance, the association of cholinergic transmission with a number of important neurological and neuromuscular diseases in the central and peripheral nervous systems., (© 2021 International Society for Neurochemistry.)

Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review was to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre‐registration of a review protocol, we systematically searched the PubMed, EMBASE, and Cochrane databases for literature covering themes of 'lactate', 'the brain', and 'microcirculation'. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. Twenty‐eight papers were identified, 18 of which were in vivo animal experiments (65%), four on human studies (14%), and six on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose‐dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD+/NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose‐dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. Open Science Badges: This article has received a badge for *Pre‐registration* because it made the data publicly available. The data can be accessed at www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer%5flactate%5fprotocol.aspx. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. This systematic review evaluated the role of lactate in the cerebral microcirculation across in vitro, in vivo, and clinical studies. We identified that when administered exogenously, at 5 mmol/kg or higher, lactate is an initiator of cerebral hyperemia and acts as an augmenter of functional hyperemia at lower doses. These findings shine light on novel aspects of lactate biochemistry in the brain. This manuscript was awarded with the Pre‐registration Badge. The pre‐registration protocol can be accessed at http://www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer%5flactate%5fprotocol.aspx. For more information see: https://cos.io/our-services/open-science-badges/ [ABSTRACT FROM AUTHOR]

The first description of Alzheimer's disease (AD) was made in 1907 by Alois Alzheimer (Allgemeine Zeitschrift fur Psyciatrie und Psychisch-Gerichtliche Medizin 64, 3, 1907), although other contemporary physicians had made similar, and rather more complete, assessments of the neuropathological changes present in the AD brain (Fischer, Monatsschr Psychiat Neurol 22, 17, 1907). Our knowledge of AD has increased dramatically and continues to accelerate. This year is 25 years after the publication of a series of papers that, in various ways, articulated the amyloid cascade hypothesis (ACH) for AD (Beyreuther and Masters, Brain Pathol 1, 241-251, 1991; Hardy and Allsop, Trends Pharmacol Sci 12, 383-388, 1991; Selkoe, Neuron 6, 487-498, 1991; Hardy and Higgins, Science 256, 184-185, 1992). This review will cover some familiar territory, but we shall also place the ACH into a wider context, compare it with other hypotheses for AD, explore the evolution of the hypothesis to encompass new findings, and determine, irrespective of the merits of the hypothesis itself, whether it has been useful for the research field, both in academia and in industry. Finally, we shall review how the ACH has led to a number of therapeutic approaches, all of which have, to date, failed to reach their primary efficacy end-points in clinical trials and reflect upon what the future may hold. We review the amyloid cascade hypothesis (ACH) and compare it with other hypotheses that have been posited to explain the initiation and progression Alzheimer's disease. We document the data that support the ACH, and also reflect upon its deficiencies. We list the recent clinical failures of amyloidocentric drugs and anticipate the results that new therapeutic approaches may deliver. This article is part of the 60th Anniversary special issue., (© 2016 International Society for Neurochemistry.)

A highly challenging question in neuroscience is to understand how aminergic neural circuits contribute to the planning and execution of behaviors, including the generation of olfactory memories. In this regard, electrophysiological techniques like Local Field Potential or imaging methods have been used to answer questions relevant to cell and circuit physiology in different animal models, such as the fly Drosophila melanogaster. However, these techniques do not provide information on the neurochemical identity of the circuits of interest. Different approaches including fast scan cyclic voltammetry, allow researchers to identify and quantify in a timely fashion the release of endogenous neuroactive molecules, but have been only used in in vitro Drosophila brain preparations. Here, we report a procedure to record for the first time the release of endogenous amines –dopamine, serotonin and octopamine‐ in adult fly brain in vivo, by fast scan cyclic voltammetry. As a proof of principle, we carried out recordings in the calyx region of the Mushroom Bodies, the brain area mainly associated to the generation of olfactory memories in flies. By using principal component regression in normalized training sets for in vivo recordings, we detect an increase in octopamine and serotonin levels in response to electric shock and olfactory cues respectively. This new approach allows the study of dynamic changes in amine neurotransmission that underlie complex behaviors in Drosophila and shed new light on the contribution of these amines to olfactory processing in this animal model. [ABSTRACT FROM AUTHOR]

In adult rats, omega‐6 linoleic acid (LA, 18:2n‐6) serves as a precursor to oxidized LA metabolites (OXLAMs) known to regulate multiple signaling processes in the brain. However, little is known regarding the levels or role(s) of LA and its metabolites during brain development. To address this gap, fatty acids within various brain lipid pools, and their oxidized metabolites (oxylipins) were quantified in brains from 1‐day‐old male and female pups using gas chromatography and liquid chromatography coupled to tandem mass spectrometry, respectively. Primary neuron‐glia co‐cultures derived from postnatal day 0–1 male and female rat neocortex were exposed to vehicle (0.1% ethanol), LA, the OXLAM 13‐hydroxyoctadecadienoic acid (13‐HODE), or prostaglandin E2 at 10–1000 nM for 48 h to test their effects on neuronal morphology. In both male and female pups, LA accounted for 1–3% of fatty acids detected in brain phospholipids and cholesteryl esters. It was not detected in triacylglycerols, and free fatty acids. Unesterified OXLAMs constituted 47–53% of measured unesterified oxylipins in males and females (vs. ~5–7% reported in adult rat brain). Of these, 13‐HODE was the most abundant, accounting for 30–33% of measured OXLAMs. Brain fatty acid and OXLAM concentrations did not differ between sexes. LA and 13‐HODE significantly increased axonal outgrowth. Separate analyses of cultures derived from male versus female pups revealed that LA at 1, 50, and 1000 nM, significantly increased axonal outgrowth in female but not male cortical neurons, whereas 13‐HODE at 100 nM significantly increased axonal outgrowth in male but not female cortical neurons. prostaglandin E2 did not alter neuronal outgrowth in either sex. This study demonstrates that OXLAMs constitute the majority of unesterified oxylipins in the developing rat brain despite low relative abundance of their LA precursor, and highlights a novel role of LA and 13‐HODE in differentially influencing neuronal morphogenesis in the developing male and female brain. [ABSTRACT FROM AUTHOR]

High‐mobility group box‐1 (HMGB‐1) acts as a pro‐inflammatory cytokine contributing to the occurrence of many central inflammatory and infectious disorders. Brain mast cells (MCs) are the first responders to peripheral inflammatory stimulation because of their rapid response to external stimuli coupled with their release of preformed and newly synthesized reactive chemicals. Little is known about the involvement of brain MCs in the pro‐inflammatory effects of HMGB‐1 on the central nervous system (CNS). Thus, we investigated the activation process of MCs by HMGB‐1 and explored whether this process is involved in the pro‐inflammatory effects of HMGB‐1 on the CNS. In this study, we used P815 cells to study the activating role of HMGB‐1 on MCs and to explore its potential mechanism in vitro. In an in vivo study, adult male Sprague‐Dawley rats received i.c.v. injection of sterile saline or cromoglycate (stabilizer of MCs) 30 min prior to i.p. injection of HMGB‐1. Increased levels of tumor necrosis factor and IL‐1β were observed in the P815 cells, as well as in the rats' brains, after HMGB‐1 treatment. Pretreatment with the receptor of advanced glycation endproducts (RAGE)‐siRNA inhibited the HMGB‐1‐induced inflammatory process in the P815 cells. Activation of the RAGE/nuclear factor‐κB (NF‐κB) pathway was observed in both the P815 cells and rats' brains. In addition, HMGB‐1 induced the accumulation of brain MCs in the hippocampal CA1 region, and the blood–brain barrier was disrupted. Pretreatment with cromoglycate, a stabilizer of MCs, mitigated these HMGB‐1‐induced pro‐inflammatory processes in rats. These findings indicate that brain MCs are involved in the pro‐inflammatory effect of HMGB‐1 on the CNS, probably via activating the RAGE/NF‐κB pathway. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal pathological glycosaminoglycans, cellular dysfunction and widespread inflammation, resulting in progressive cognitive and motor decline. Lysosomes are important mediators of immune cell function, and therefore accumulation of glycosaminoglycans (GAGs) and other abnormal substrates could affect immune function and directly impact on disease pathogenesis. This review summarises current knowledge with regard to inflammation in mucopolysaccharidosis, with an emphasis on the brain and outlines a potential role for GAGs in induction of inflammation. We propose a model by which the accumulation of GAGs and other factors may impact on innate immune signalling with particular focus on the Toll‐like receptor 4 pathway. Innate immunity appears to have a dominating role in mucopolysaccharidosis; however, furthering understanding of innate immune signalling would have significant impact on highlighting novel anti‐inflammatory therapeutics for use in mucopolysaccharide diseases. This article is part of the Special Issue "Lysosomal Storage Disorders". Mucopolysaccharidoses are lysosomal storage disorders characterised by accumulation of abnormal glycosaminoglycans, cellular dysfunction and widespread inflammation. Lysosomes are critical mediators of immunity, and therefore lysosomal substrate accumulation could affect immune function and directly impact on disease pathogenesis. In this review, we summarise the current knowledge with regard to inflammation in mucopolysaccharidosis with an emphasis on the brain. We propose a model by which the accumulation of GAGs may impact on innate immune signalling with particular focus on the TLR4 pathway. Furthering our understanding of inflammatory signalling in lysosomal storage disease would have significant impact on highlighting novel anti‐inflammatory therapeutics. This article is part of the Special Issue "Lysosomal Storage Disorders". [ABSTRACT FROM AUTHOR]

Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine ( O-Glc NAc) regulates protein homeostasis. The O-Glc NAc modification is highly abundant in the mammalian brain and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. C. elegans, Drosophila, and mouse models harboring O-Glc NAc transferase- and O-Glc NAcase-knockout alleles have helped define the role O-Glc NAc plays in development as well as age-associated neurodegenerative disease. These enzymes add and remove the single monosaccharide from protein serine and threonine residues, respectively. Blocking O-Glc NAc cycling is detrimental to mammalian brain development and interferes with neurogenesis, neural migration, and proteostasis. Findings in C. elegans and Drosophila model systems indicate that the dynamic turnover of O-Glc NAc is critical for maintaining levels of key transcriptional regulators responsible for neurodevelopment cell fate decisions. In addition, pathways of autophagy and proteasomal degradation depend on a transcriptional network that is also reliant on O-Glc NAc cycling. Like the quality control system in the endoplasmic reticulum which uses a 'mannose timer' to monitor protein folding, we propose that cytoplasmic proteostasis relies on an ' O-Glc NAc timer' to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O-Glc NAc-dependent developmental alterations impact metabolism and growth of the developing mouse embryo and persist into adulthood. Brain-selective knockout mouse models will be an important tool for understanding the role of O-Glc NAc in the physiology of the brain and its susceptibility to neurodegenerative injury. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors ( SSRIs) are the most frequently prescribed antidepressants. However, a major concern is their delayed onset of action, which is hypothesized to be associated with the time required for serotonin (5- HT) autoreceptors to desensitize, which should be reflected by actual neurochemical changes. Numerous in vivo microdialysis studies have been published that report on 5- HT levels in different brain sites following SSRI administration. Here, we performed a meta-analysis on dynamic changes of 5- HT neurotransmission during the course of chronic SSRI treatment. We conducted a meta-analysis on research articles of 5- HT neurotransmission measured by in vivo microdialysis in rat brain after subchronic and chronic SSRI administrations. In total, data from 42 microdialysis studies (798 rats) were analyzed. Within the first week of SSRI treatment, extracellular 5- HT concentrations drop in frontal cortex. Over the next 2 weeks of treatment, a linear increase in extracellular 5- HT levels up to 350% of prior treatment baseline is evident ( n = 269). However, in hippocampus, prefrontal cortex, nucleus accumbens, and ventral tegmental area we found increased 5- HT levels within the first 3 days of SSRI administration. The time course of 5- HT dynamics in frontal cortex is in line with the hypothesis that 5- HT autoreceptors desensitize over 2-3 weeks of SSRI treatment and thereby enhanced extracellular 5- HT levels ensue. Yet, in other regions we did not find evidence supporting the traditional autoreceptor-mediated feedback loops hypothesis and thus other neurobiological adaptation mechanisms may also play a role in the delayed onset of SSRI action. [ABSTRACT FROM AUTHOR]

Organophosphorus ( OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase ( AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine ( ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. This is an article for the . [ABSTRACT FROM AUTHOR]

Accumulation of ceramide is implicated in mediating the cellular responses to stress and aberrant sphingolipid metabolism is frequently associated with metabolic and neurodegenerative diseases. It is often assumed that (i) peripheral disturbances in sphingolipid concentrations are reflective of processes occurring in the brain, or (ii) circulating sphingolipids directly influence cerebral sphingolipid abundance. In order to address these assumptions, this study explores, in a physiological system, the metabolic pathways regulating sphingolipid metabolism in the brain and plasma of mice. Male C57Bl/6 were maintained on a low fat (control diet) or saturated fat enriched ( SFA) diet with, or without the provision of sphingolipid modulating agents. Following 6 months of feeding, the abundance of seven sphingolipid classes was assessed by LC- ESI- MS/ MS in the hippocampus ( HPF), cerebral cortex ( CTX), and plasma. Long-term consumption of the SFA diet increased ceramide and dihydroceramide in the plasma. Inhibiting de novo synthesis ameliorated this effect, while inhibition of acidic sphingomyelinase, or the sphingosine-1-phosphate receptor agonist did not. SFA feeding did not influence sphingolipid levels in either the HPF or CTX. De novo synthesis inhibition reduced ceramide in the CTX, while treatment with a sphingosine-1-phosphate receptor agonist reduced ceramides in the HPF. Analysis of the individual ceramide species revealed the effects were chain-length dependent. Both positive and negative correlations were observed between plasma and HPF/ CTX ceramide species. The findings in this study show that HPF and CTX sphingolipid concentration are influenced by distinct pathways, independent of peripheral sphingolipid concentration. [ABSTRACT FROM AUTHOR]

The endocannabinoid system shifts energy balance toward storage and fat accumulation, especially in the context of diet-induced obesity. Relatively little is known about factors outside the central nervous system that may mediate the effect of high-fat diet ( HFD) on brain endocannabinoid levels. One candidate is the liver fatty acid binding protein ( FABP1), a cytosolic protein highly prevalent in liver, but not detected in brain, which facilitates hepatic clearance of fatty acids. The impact of Fabp1 gene ablation ( LKO) on the effect of high-fat diet ( HFD) on brain and plasma endocannabinoid levels was examined and data expressed for each parameter as the ratio of high-fat diet/control diet. In male wild-type mice, HFD markedly increased brain N-acylethanolamides, but not 2-monoacylglycerols. LKO blocked these effects of HFD in male mice. In female wild-type mice, HFD slightly decreased or did not alter these endocannabinoids as compared with male wild type. LKO did not block the HFD effects in female mice. The HFD-induced increase in brain arachidonic acid-derived arachidonoylethanolamide in males correlated with increased brain-free and total arachidonic acid. The ability of LKO to block the HFD-induced increase in brain arachidonoylethanolamide correlated with reduced ability of HFD to increase brain-free and total arachidonic acid in males. In females, brain-free and total arachidonic acid levels were much less affected by either HFD or LKO in the context of HFD. These data showed that LKO markedly diminished the impact of HFD on brain endocannabinoid levels, especially in male mice. [ABSTRACT FROM AUTHOR]

Liver fatty acid-binding protein ( FABP1, L- FABP) has high affinity for and enhances uptake of arachidonic acid ( ARA, C20:4, n-6) which, when esterified to phospholipids, is the requisite precursor for synthesis of endocannabinoids ( EC) such as arachidonoylethanolamide ( AEA) and 2-arachidonoylglycerol (2- AG). The brain derives most of its ARA from plasma, taking up ARA and transporting it intracellularly via cytosolic fatty acid-binding proteins ( FABPs 3,5, and 7) localized within the brain. In contrast, the much more prevalent cytosolic FABP1 is not detectable in the brain but is instead highly expressed in the liver. Therefore, the possibility that FABP1 outside the central nervous system may regulate brain AEA and 2- AG was examined in wild-type ( WT) and FABP1 null ( LKO) male mice. LKO increased brain levels of AA-containing EC ( AEA, 2- AG), correlating with increased free and total ARA in brain and serum. LKO also increased brain levels of non- ARA that contain potentiating endocannabinoids ( EC*) such as oleoyl ethanolamide ( OEA), PEA, 2- OG, and 2- PG. Concomitantly, LKO decreased serum total ARA-containing EC, but not non- ARA endocannabinoids. LKO did not elicit these changes in the brain EC and EC* as a result of compensatory up-regulation of brain protein levels of enzymes in EC synthesis ( NAPEPLD, DAGLα) or cytosolic EC chaperone proteins ( FABPs 3, 5, 7, SCP-2, HSP70), or cannabinoid receptors ( CB1, TRVP1). These data show for the first time that the non- CNS fatty acid-binding protein FABP1 markedly affected brain levels of both ARA-containing endocannabinoids ( AEA, 2- AG) as well as their non- ARA potentiating endocannabinoids. [ABSTRACT FROM AUTHOR]

Hyperexcitability of the hippocampus is a commonly observed phenomenon in the years preceding a diagnosis of Alzheimer's disease ( AD). Our previous work suggests a dysregulation in glutamate neurotransmission may mediate this hyperexcitability, and glutamate dysregulation correlates with cognitive deficits in the rTg(TauP301L)4510 mouse model of AD. To determine whether improving glutamate regulation would attenuate cognitive deficits and AD-related pathology, TauP301L mice were treated with riluzole (~ 12.5 mg/kg/day p.o.), an FDA-approved drug for amyotrophic lateral sclerosis that lowers extracellular glutamate levels. Riluzole-treated TauP301L mice exhibited improved performance in the water radial arm maze and the Morris water maze, associated with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus, cornu ammonis 3 ( CA3), and cornu ammonis 1 ( CA1) regions of the hippocampus. Riluzole also attenuated the TauP301L-mediated increase in hippocampal vesicular glutamate transporter 1, which packages glutamate into vesicles and influences glutamate release; and the TauP301L-mediated decrease in hippocampal glutamate transporter 1, the major transporter responsible for removing glutamate from the extracellular space. The TauP301L-mediated reduction in PSD-95 expression, a marker of excitatory synapses in the hippocampus, was also rescued by riluzole. Riluzole treatment reduced total levels of tau, as well as the pathological phosphorylation and conformational changes in tau associated with the P301L mutation. These findings open new opportunities for the development of clinically applicable therapeutic approaches to regulate glutamate in vulnerable circuits for those at risk for the development of AD. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acid ( LPA) is a signaling molecule that binds to six known G protein-coupled receptors: LPA1- LPA6. LPA evokes several responses in the CNS, including cortical development and folding, growth of the axonal cone and its retraction process. Those cell processes involve survival, migration, adhesion proliferation, differentiation, and myelination. The anatomical localization of LPA1 is incompletely understood, particularly with regard to LPA binding. Therefore, we have used functional [35S] GTPγS autoradiography to verify the anatomical distribution of LPA1 binding sites in adult rodent and human brain. The greatest activity was observed in myelinated areas of the white matter such as corpus callosum, internal capsule and cerebellum. Ma LPA1-null mice (a variant of LPA1-null) lack [35S] GTPγS basal binding in white matter areas, where the LPA1 receptor is expressed at high levels, suggesting a relevant role of the activity of this receptor in the most myelinated brain areas. In addition, phospholipid precursors of LPA were localized by MALDI- IMS in both rodent and human brain slices identifying numerous species of phosphatides and phosphatidylcholines. Both phosphatides and phosphatidylcholines species represent potential LPA precursors. The anatomical distribution of these precursors in rodent and human brain may indicate a metabolic relationship between LPA and LPA1 receptors. [ABSTRACT FROM AUTHOR]