Showing papers in "Neuroscience Bulletin in 2014"

Oxidative stress in Alzheimer’s disease

Abstract: Oxidative stress plays a significant role in the pathogenesis of Alzheimer’s disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.

Disrupted structural and functional brain connectomes in mild cognitive impairment and Alzheimer's disease.

Abstract: Alzheimer’s disease (AD) is the most common type of dementia, comprising an estimated 60–80% of all dementia cases. It is clinically characterized by impairments of memory and other cognitive functions. Previous studies have demonstrated that these impairments are associated with abnormal structural and functional connections among brain regions, leading to a disconnection concept of AD. With the advent of a combination of non-invasive neuroimaging (structural magnetic resonance imaging (MRI), diffusion MRI, and functional MRI) and neurophysiological techniques (electroencephalography and magnetoencephalography) with graph theoretical analysis, recent studies have shown that patients with AD and mild cognitive impairment (MCI), the prodromal stage of AD, exhibit disrupted topological organization in large-scale brain networks (i.e., connectomics) and that this disruption is significantly correlated with the decline of cognitive functions. In this review, we summarize the recent progress of brain connectomics in AD and MCI, focusing on the changes in the topological organization of large-scale structural and functional brain networks using graph theoretical approaches. Based on the two different perspectives of information segregation and integration, the literature reviewed here suggests that AD and MCI are associated with disrupted segregation and integration in brain networks. Thus, these connectomics studies open up a new window for understanding the pathophysiological mechanisms of AD and demonstrate the potential to uncover imaging biomarkers for clinical diagnosis and treatment evaluation for this disease.

M1 muscarinic acetylcholine receptor in Alzheimer's disease.

Abstract: The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer's disease (AD). Muscarinic acetylcholine receptors (mAChRs) mediate acetylcholine-induced neurotransmission and five mAChR subtypes (M1-M5) have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists for AD treatment.

Cerebrospinal fluid biomarkers of Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is a fatal neurodegenerative disorder that takes about a decade to develop, making early diagnosis possible. Clinically, the diagnosis of AD is complicated, costly, and inaccurate, so it is urgent to find specific biomarkers. Due to its multifactorial nature, a panel of biomarkers for the multiple pathologies of AD, such as cerebral amyloidogenesis, neuronal dysfunction, synapse loss, oxidative stress, and inflammation, are most promising for accurate diagnosis. Highly sensitive and high-throughput proteomic techniques can be applied to develop a panel of novel biomarkers for AD. In this review, we discuss the metabolism and diagnostic performance of the well-established core candidate cerebrospinal fluid (CSF) biomarkers (β-amyloid, total tau, and hyperphosphorylated tau). Meanwhile, novel promising CSF biomarkers, especially those identified by proteomics, updated in the last five years are also extensively discussed. Furthermore, we provide perspectives on how biomarker discovery for AD is evolving.

Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass

Abstract: Considerable debate and controversy surround the cause(s) of Alzheimer's disease (AD). To date, several theories have gained notoriety, however none is universally accepted. In this review, we provide evidence for the oxidative stress-induced AD cascade that posits aged mitochondria as the critical origin of neurodegeneration in AD.

Apolipoprotein E, amyloid-beta, and neuroinflammation in Alzheimer’s disease

Abstract: Alzheimer’s disease (AD) is characterized by the accumulation and deposition of amyloid-beta (Aβ) peptides in the brain. Neuroinflammation occurs in the AD brain and plays a critical role in the neurodegenerative pathology. Particularly, Aβ evokes an inflammatory response that leads to synaptic dysfunction, neuronal death, and neurodegeneration. Apolipoprotein E (ApoE) proteins are involved in cholesterol transport, Aβ binding and clearance, and synaptic functions in the brain. The ApoE4 isoform is a key risk factor for AD, while the ApoE2 isoform has a neuroprotective effect. However, studies have reached different conclusions about the roles of the isoforms; some show that both ApoE3 and ApoE4 have anti-inflammatory effects, while others show that ApoE4 causes a predisposition to inflammation or promotes an inflammatory response following lipopolysaccharide treatment. These discrepancies may result from the differences in models, cell types, experimental conditions, and inflammatory stimuli used. Further, little was known about the role of ApoE isoforms in the Aβ-induced inflammatory response and in the neuroinflammation of AD. Our recent work showed that ApoE isoforms differentially regulate and modify the Aβ-induced inflammatory response in neural cells, with ApoE2 suppressing and ApoE4 promoting the response. In this article, we review the roles, mechanisms, and interrelations among Aβ, ApoE, and neuroinflammation in AD.

Regulation of alternative splicing of tau exon 10

Abstract: The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer’s disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4Rtau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology) only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.

Tau-induced neurodegeneration: mechanisms and targets.

Abstract: The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau’s functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifications can alter tau’s biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.

Lipid metabolism in Alzheimer’s disease

Abstract: Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis.

Deregulation of brain insulin signaling in Alzheimer’s disease

Abstract: Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer’s disease (AD). In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid β precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.

MiR-206 decreases brain-derived neurotrophic factor levels in a transgenic mouse model of Alzheimer's disease.

Abstract: MicroRNA alterations have been reported in patients with Alzheimer's disease (AD) and AD mouse models. We now report that miR-206 is upregulated in the hippocampal tissue, cerebrospinal fluid, and plasma of embryonic APP/PS1 transgenic mice. The increased miR-206 downregulates the expression of brain-derived neurotrophic factor (BDNF). BDNF is neuroprotective against cell death after various insults, but in embryonic and newborn APP/PS1 mice it is decreased. Thus, a specific microRNA alteration may contribute to AD pathology by downregulating BDNF.

Inflammation: a mechanism of depression?

Abstract: In recent decades, major depression has become more prevalent and research has shown that immune activation and cytokine production may be involved. This review is mainly focused on the contribution of inflammation to depression. We first briefly introduce the inflammatory biomarkers of depression, then discuss the sources of cytokines in the brain, and finally describe the neuroimmunological mechanisms underlying the association between inflammation and depression.

Store-operated calcium entry in neuroglia.

Abstract: Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca(2+) signals that define the "Ca(2+) excitability" of glia. In mammalian glial cells the major source of Ca(2+) for this excitability is the lumen of the endoplasmic reticulum (ER), which is ultimately (re)filled from the extracellular space. This occurs via store-operated Ca(2+) entry (SOCE) which is supported by a specific signaling system connecting the ER with plasmalemmal Ca(2+) entry. Here, emptying of the ER Ca(2+) store is necessary and sufficient for the activation of SOCE, and without Ca(2+) influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca(2+) sensors, such as stromal interaction molecule, and possibly ER Ca(2+) pumps (of the SERCA type). There are at least two sets of plasmalemmal channels mediating SOCE, the Ca(2+)-release activated channels, Orai, and transient receptor potential (TRP) channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca(2+) signal observed following stimulation of metabotropic receptors on glial cells.

Microtubule dynamics in axon guidance

Abstract: Precise modulation of the cytoskeleton is involved in a variety of cellular processes including cell division, migration, polarity, and adhesion. In developing post-mitotic neurons, extracellular guidance cues not only trigger signaling cascades that act at a distance to indirectly regulate microtubule distribution, and assembly and disassembly in the growth cone, but also directly modulate microtubule stability and dynamics through coupling of guidance receptors with microtubules to control growth-cone turning. Microtubule-associated proteins including classical microtubule-associated proteins and microtubule plus-end tracking proteins are required for modulating microtubule dynamics to influence growth-cone steering. Multiple key signaling components, such as calcium, small GTPases, glycogen synthase kinase-3β, and c-Jun N-terminal kinase, link upstream signal cascades to microtubule stability and dynamics in the growth cone to control axon outgrowth and projection. Understanding the functions and regulation of microtubule dynamics in the growth cone provides new insights into the molecular mechanisms of axon guidance.

Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease.

Abstract: Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer's disease (AD); however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented.

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats.

Abstract: Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-inflammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphaeroides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawal-induced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawal-induced pain hypersensitivity.

Clusterin in Alzheimer's disease: a player in the biological behavior of amyloid-beta.

Abstract: Alzheimer’s disease (AD) remains a major killer, and although its pathogenesis varies, one dominant feature is an increase in the expression, formation, and sedimentation of senile plaques of amyloid-beta (Aβ) peptides in the brain. The chaperone protein clusterin has, since its first discovery at the end of the 20th century, been labeled as a cytoprotector. However, epigenetic studies showing that clusterin is associated with the severity and risk of AD, especially in the hippocampus, triggered studies to clarify its role in the pathogenesis of AD. It is true that clusterin can inhibit the aggregation of Aβ and therefore prevent further formation of senile plaques in the AD brain, yet it induces the formation of soluble forms of Aβ which are toxic to neurons. Another problematic finding is that clusterin is involved in a pathway through which Aβ has neurodegenerative effects intracellularly. Although the role of clusterin in the pathogenesis of AD is still not clear, this review specifically discusses the interactions between clusterin and Aβ, to open up the possibility of a potential therapeutic approach for treating AD.

The myelin membrane-associated enzyme 2',3'-cyclic nucleotide 3'-phosphodiesterase: on a highway to structure and function.

Abstract: The membrane-anchored myelin enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) was discovered in the early 1960s and has since then troubled scientists with its peculiar catalytic activity and high expression levels in the central nervous system. Despite decades of research, the actual physiological relevance of CNPase has only recently begun to unravel. In addition to a role in myelination, CNPase is also involved in local adenosine production in traumatic brain injury and possibly has a regulatory function in mitochondrial membrane permeabilization. Although research focusing on the CNPase phosphodiesterase activity has been helpful, several open questions concerning the protein function in vivo remain unanswered. This review is focused on past research on CNPase, especially in the fields of structural biology and enzymology, and outlines the current understanding regarding the biochemical and physiological significance of CNPase, providing ideas and directions for future research.

Role of cortical spreading depression in the pathophysiology of migraine.

Abstract: A migraine is a recurring neurological disorder characterized by unilateral, intense, and pulsatile headaches. In one-third of migraine patients, the attacks are preceded by a visual aura, such as a slowly-propagating scintillating scotoma. Migraine aura is thought to be a result of the neurovascular phenomenon of cortical spreading depression (SD), a self-propagating wave of depolarization that spreads across the cerebral cortex. Several animal experiments have demonstrated that cortical SD causes intracranial neurogenic inflammation around the meningeal blood vessels, such as plasma protein extravasation and pro-inflammatory peptide release. Cortical SD has also been reported to activate both peripheral and central trigeminal nociceptive pathways. Although several issues remain to be resolved, recent evidence suggests that cortical SD could be the initial trigger of intracranial neurogenic inflammation, which then contributes to migraine headaches via subsequent activation of trigeminal afferents.

Influence of deep brain stimulation of the subthalamic nucleus on cognitive function in patients with Parkinson’s disease

Abstract: Deep brain stimulation (DBS) is an effective technique for treating Parkinson's disease (PD) in the middle and advanced stages. The subthalamic nucleus (STN) is the most common target for clinical treatment using DBS. While STN-DBS can significantly improve motor symptoms in PD patients, adverse cognitive effects have also been reported. The specific effects of STN-DBS on cognitive function and the related mechanisms remain unclear. Thus, it is imperative to identify the influence of STN-DBS on cognition and investigate the potential mechanisms to provide a clearer view of the various cognitive sequelae in PD patients. For this review, a literature search was performed using the following inclusion criteria: (1) at least 10 patients followed for a mean of at least 6 months after surgery since the year 2006; (2) pre- and postoperative cognitive data using at least one standardized neuropsychological scale; and (3) adequate reporting of study results using means and standard deviations. Of ∼170 clinical studies identified, 25 cohort studies (including 15 self-controlled studies, nine intergroup controlled studies, and one multi-center, randomized control experiment) and one meta-analysis were eligible for inclusion. The results suggest that the precise mechanism of the changes in cognitive function after STN-DBS remains obscure, but STN-DBS certainly has effects on cognition. In particular, a progressive decrease in verbal fluency after STN-DBS is consistently reported and although executive function is unchanged in the intermediate stage postoperatively, it tends to decline in the early and later stages. However, these changes do not affect the improvements in quality of life. STN-DBS seems to be safe with respect to cognitive effects in carefully-selected patients during a follow-up period from 6 months to 9 years.

Generation of a monkey with MECP2 mutations by TALEN-based gene targeting

Abstract: Gene editing in model organisms has provided critical insights into brain development and diseases. Here, we report the generation of a cynomolgus monkey (Macaca fascicularis) carrying MECP2 mutations using transcription activator-like effector nucleases (TALENs)-mediated gene targeting. After injecting TALENs mRNA into monkey zygotes achieved by in vitro fertilization and embryo transplantation into surrogate monkeys, we obtained one male newborn monkey with an MECP2 deletion caused by frameshifting mutation in various tissues. The monkey carrying the MECP2 mutation failed to survive after birth, due to either the toxicity of TALENs or the critical requirement of MECP2 for neural development. The level of MeCP2 protein was essentially depleted in the monkey's brain. This study demonstrates the feasibility of introducing genetic mutations in non-human primates by site-specific gene-editing methods.

Dysfunction of hippocampal interneurons in epilepsy.

Abstract: Gamma-amino-butyric acid (GABA)-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.

Dysfunctional autophagy in Alzheimer's disease: pathogenic roles and therapeutic implications.

Abstract: Neuronal autophagy is essential for neuronal survival and the maintenance of neuronal homeostasis. Increasing evidence has implicated autophagic dysfunction in the pathogenesis of Alzheimer’s disease (AD). The mechanisms underlying autophagic failure in AD involve several steps, from autophagosome formation to degradation. The effect of modulating autophagy is context-dependent. Stimulation of autophagy is not always beneficial. During the implementation of therapies that modulate autophagy, the nature of the autophagic defect, the timing of intervention, and the optimal level and duration of modulation should be fully considered.

Uric formaldehyde levels are negatively correlated with cognitive abilities in healthy older adults.

Abstract: Recent studies have shown that the abnormal accumulation of endogenous formaldehyde could be a critical factor in age-related cognitive decline. The aim of this study was to estimate the correlation between uric formaldehyde and general cognitive abilities in a community-based elderly population, and to measure the extent and direction in which the correlation varied with demographic characteristics. Using a double-blind design, formaldehyde in human urine was analyzed by high-performance liquid chromatography (n = 604), and general cognitive abilities were measured using the Montreal Cognitive Assessment (MoCA). Demographic characteristics, in terms of age, gender, residential region, and education were taken into consideration. We found that uric formaldehyde levels were inversely correlated with the MoCA score, and the concentration varied with demographic features: higher odds of a high formaldehyde level occurred among the less educated and those living in old urban or rural areas. In cytological experiments, the level of cellular formaldehyde released into the medium increased as SH-SY5Y and BV2 cells were incubated for three days. Formaldehyde in excess impaired the processes of N2a cells and neurites of primary cultured rat hippocampal cells. However, removal of formaldehyde markedly rescued and regenerated the processes of N2a cells. These results demonstrated a negative correlation between the endogenous formaldehyde and general cognitive abilities. High formaldehyde levels could be a risk factor for cognitive impairment in older adults, and could be developed as a non-invasive marker for detection and monitoring of age-related cognitive impairment.

Hyposmia: a possible biomarker of Parkinson’s disease

Abstract: Hyposmia, identified as reduced sensitivity to odor, is a common non-motor symptom of Parkinson's disease (PD) that antedates the typical motor symptoms by several years. It occurs in ∼90% of early-stage cases of PD. In addition to the high prevalence, the occurrence of hyposmia may also predict a higher risk of PD. Investigations into hyposmia and its relationship with PD may help elucidate the underlying pathogenic mechanisms. This review provides an update of olfactory dysfunction in PD and its potential as a biomarker for this devastating disease.

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats.

Abstract: Amyloid β-peptide (Aβ) has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer’s disease (AD). Humanin (HN) is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism(s) by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study, we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1–42. HN also attenuated Aβ1–42-induced tau hyperphosphorylation, apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A (PP2A) catalytic subunit and thereby activating PP2A. HN also inhibited apoptosis and reduced the oxidative stress induced by Aβ1–42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1–42-induced AD-like pathological changes and memory deficits.

Development of (18)F-labeled radiotracers for neuroreceptor imaging with positron emission tomography.

Abstract: Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including genetically-engineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.

MeCP2: multifaceted roles in gene regulation and neural development.

Abstract: Methyl-CpG-binding protein 2 (MeCP2) is a classic methylated-DNA-binding protein, dysfunctions of which lead to various neurodevelopmental disorders such as Rett syndrome and autism spectrum disorder Initially recognized as a transcriptional repressor, MeCP2 has been studied extensively and its functions have been expanded dramatically in the past two decades Recently, it was found to be involved in gene regulation at the post-transcriptional level MeCP2 represses nuclear microRNA processing by interacting directly with the Drosha/DGCR8 complex In addition to its multifaceted functions, MeCP2 is remarkably modulated by posttranslational modifications such as phosphorylation, SUMOylation, and acetylation, providing more regulatory dimensions to its functions The role of MeCP2 in the central nervous system has been studied extensively, from neurons to glia Future investigations combining molecular, cellular, and physiological methods are necessary for defining the roles of MeCP2 in the brain and developing efficient treatments for MeCP2-related brain disorders

Grey-matter volume as a potential feature for the classification of Alzheimer's disease and mild cognitive impairment: an exploratory study

Abstract: Specific patterns of brain atrophy may be helpful in the diagnosis of Alzheimer’s disease (AD). In the present study, we set out to evaluate the utility of grey-matter volume in the classification of AD and amnestic mild cognitive impairment (aMCI) compared to normal control (NC) individuals. Voxel-based morphometric analyses were performed on structural MRIs from 35 AD patients, 27 aMCI patients, and 27 NC participants. A two-sample two-tailed t-test was computed between the NC and AD groups to create a map of abnormal grey matter in AD. The brain areas with significant differences were extracted as regions of interest (ROIs), and the grey-matter volumes in the ROIs of the aMCI patients were included to evaluate the patterns of change across different disease severities. Next, correlation analyses between the grey-matter volumes in the ROIs and all clinical variables were performed in aMCI and AD patients to determine whether they varied with disease progression. The results revealed significantly decreased grey matter in the bilateral hippocampus/parahippocampus, the bilateral superior/middle temporal gyri, and the right precuneus in AD patients. The grey-matter volumes were positively correlated with clinical variables. Finally, we performed exploratory linear discriminative analyses to assess the classifying capacity of grey-matter volumes in the bilateral hippocampus and parahippocampus among AD, aMCI, and NC. Leave-one-out crossvalidation analyses demonstrated that grey-matter volumes in hippocampus and parahippocampus accurately distinguished AD from NC. These findings indicate that grey-matter volumes are useful in the classification of AD.

Innate immune responses regulate morphogenesis and degeneration: roles of Toll-like receptors and Sarm1 in neurons

Abstract: The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors (TLRs) and their adaptor proteins (Sarm1, Myd88, and Trif), and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function. In this article, we review the recent findings on the involvement of TLRs and Sarm1 in controlling neuronal morphogenesis and neurodegeneration. Abnormal behaviors in TLR- and Sarm1-deficient mice are also discussed.