CD200 and its receptor, CD200 receptor (CD200R), have uniaue roles in controlling damaging inflammatory processes. At present, the only identified function for CD200 is as a ligand for CD200R. These proteins interact resulting in the activation of anti-inflammatory signaling by CD200R-expressing cells. When this interaction becomes deficient with aging or disease, chronic inflammation occurs, Experimental animal studies have demonstrated the consequences of disrupting CD200–CD200R interactions in the brain, but there have been few studies in human brains. Deficiency in neuronal CD200 may explain the chronic inflammation in human neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and multiple sclerosis; however, deficits in the microglial expression of CD200R may also be of functional significance. The purpose of this review is to assess the data regarding the role of CD200–CD200R interactions in relation to the brain in order to determine if this could be a therapeutic target for human brain diseases with inflammatory components, and what additional studies are needed.
aging; alternative activation; anti-inflammatory signaling; cell surface protein; endogenous inflammatory regulator; inflammation; neurodegenerative disease; neuropathology
progressive hearing loss; age-related hearing loss; deafness; DNFB77; hair cells; LOXHD1; stereocilia; PLAT domain
Huntington disease (HD) is a devastating illness, although its autosomal dominant genetic transmission allows a unique opportunity to study apparently healthy individuals before manifest disease. Attempts to study early disease are not unique in neurology (e.g., Mild Cognitive Impairment, Vascular Cognitive Impairment), but studying otherwise-healthy appearing individuals who will go on with nearly 99% certainty to manifest the symptoms of brain disease does provide distinct but valuable information about the true natural history of the disease. The field has witnessed an explosion of research examining possible early indicators of HD during what is now referred to as the “prodrome” of HD. A NIH study in its ninth year (PREDICT-HD) has offered a glimpse into the transition from an apparently healthy state to an obviously diseased state, and can serve as a model for many other genetic diseases, both neurological and non-neurological.
Huntington disease; diagnosis; detection; prevention; biomarkers; clinical endpoints; clinical trials
Synaptic communication is highly regulated process of contact between cells allowing information to be stored and modified. Synaptic formation and maturation is the result of interactions between intrinsic genetic/molecular factors and the external environment to establish the communication in the brain. One disorder associated with faulty synapse communication is Rett Syndrome (RTT). RTT is the leading form of severe MR in females, affecting approximately 1:10,000 females worldwide, without predisposition to any particular racial or ethnic group. Mutations in MECP2, the gene encoding methyl-CpG-binding protein-2, have been identified in more than 95% of individuals with RTT. Birth and the milestones of early development appear to be normal in individuals with RTT until approximately 6–18 months when in the subsequent months and years that follows, physical, motor, and social-cognitive development enter a period of regression. The clinical management of these individuals is extremely multifaceted, relying on collaborations of specialists and researchers from many different fields. In this critical literature review, we provide an overview of Rett Syndrome, from patient to pathophysiology with a therapeutic summary of clinical trials in RTT and preclinical studies using mouse and cell models of RTT.
Rett Syndrome; MeCP2; Neurodevelopmental Disorders; Clinical Trials
Autism spectrum disorders are neurodevelopmental disorders characterized by significant deficits in reciprocal social interactions, impaired communication and restricted, repetitive behaviors. As autism spectrum disorders are among the most heritable of neuropsychiatric disorders, much of autism research has focused on the search for genetic variants in protein-coding genes (i.e., the ‘trees’). However, no single gene can account for more than 1% of the cases of autism spectrum disorders. Yet, genome-wide association studies have often identified statistically significant associations of genetic variations in regions of DNA that do not code for proteins (i.e., intergenic regions). There is increasing evidence that such noncoding regions are actively transcribed and may participate in the regulation of genes, including genes on different chromosomes. This article summarizes evidence that suggests that the research spotlight needs to be expanded to encompass far-reaching gene-regulatory mechanisms that include a variety of epigenetic modifications, as well as noncoding RNA (i.e., the ‘forest’). Given that noncoding RNA represents over 90% of the transcripts in most cells, we may be observing just the ‘tip of the iceberg’ or the ‘edge of the forest’ in the genomic landscape of autism.
autism spectrum disorder phenotypes; ‘dark matter’ RNA; epigenetics; future therapeutic options; gene–environment interaction; genetics; new research paradigm
Treatment of visual hallucinations in neurodegenerative disorders is not well advanced. The complexity of underlying mechanisms presents a number of potential avenues for developing treatments, but also suggests that any single one may be of limited efficacy. Reducing medication, with the careful introduction of antidementia medication if needed, is the mainstay of current management. Antipsychotic medication leads to excessive morbidity and mortality and should only be used in cases of high distress that do not otherwise respond. Education, reduction of risk factors and psychological treatments have limited evidence of efficacy, but are unlikely to cause harm.
Alzheimer’s disease; amyloidopathy; Lewy body; Parkinson’s disease; synucleinopathy; tauopathy; treatment; visual hallucination
Our elderly population is growing and declines in cognitive abilities, such as memory, can be costly, because it can interfere with a person’s ability to live independently. The NMDA receptor is very important for many different forms of memory and this receptor is negatively affected by aging. This review examines the progress that has been made recently in characterizing selective vulnerabilities of different subunits and splice variants of the NMDA receptor to normal aging in C57BL/6 mice. Evidence is also presented for changes in the relationships of NMDA receptors to plasticity across aging. Recent interventions show that enhancing NMDA receptors in aged individuals is associated with improvements in memory, but mouse models of neurodegenerative diseases suggest that finding the right balance between too little and too much NMDA receptor activity will be the key to enhancing memory without inducing pathology.
frontal cortex; GluN1 (NR1; ζ1) subunit; GluN2B (NR2B; ε2) subunit; glutamate receptor; hippocampus; splice variants
In this article, we will describe the malignant synaptic growth hypothesis of Alzheimer’s disease. Originally presented in 1994, the hypothesis remains a viable model of the functional and biophysical mechanisms underlying the development and progression of Alzheimer’s disease. In this article, we will refresh the model with references to relevant empirical support that has been generated in the intervening two decades since it’s original presentation. We will include discussion of its relationship, in terms of points of alignment and points of contention, to other models of Alzheimer’s disease, including the cholinergic hypothesis and the tau and β-amyloid models of Alzheimer’s disease. Finally, we propose several falsifiable predictions made by the malignant synaptic growth hypothesis and describe the avenues of treatment that hold the greatest promise under this hypothesis.
β amyloid; acetylcholine; Alzheimer’s; computational model; dementia; excitotoxicity; long-term potentiation; neurofibrillary tangles; plasticity; tau
Current treatments for epilepsy suffer from significant limitations, including medical intractability and lack of disease-modifying or anti-epileptogenic actions. As most current seizure medications modulate ion channels and neurotransmitter receptors, more effective therapies likely need to target completely different mechanisms of action. The mammalian target of rapamycin (mTOR) pathway represents a potential novel therapeutic target for epilepsy. mTOR inhibitors can suppress seizures and prevent epilepsy in animal models of certain genetic epilepsies, such as tuberous sclerosis complex. mTOR inhibitors may also be effective in some models of acquired epilepsy related to brain injury, but these effects are more variable and dependent on a number of factors. Some clinical data suggest that mTOR inhibitors decrease seizures in tuberous sclerosis complex patients, but controlled trials are lacking and no clinical data on potential anti-epileptogenic actions exist. Future basic and clinical research will help to determine the full potential of mTOR inhibitors for epilepsy.
epilepsy; rapamycin; seizure; tuberous sclerosis
The inherited disorders of γ-amino butyric acid (GABA) metabolism require an increased index of clinical suspicion. The known genetic disorders are GABA-transaminase deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency and homocarnosinosis. A recent link has also been made between impaired GABA synthesis and nonsyndromic cleft lip, with or without cleft palate. SSADH deficiency is the most commonly occurring of the inherited disorders of neurotransmitters. The disorder has a nonspecific phenotype with myriad neurological and psychiatric manifestations, and usually has a nonprogressive temporal course. Diagnosis is made by the detection of γ-hydroxybutyrate excretion on urine organic acid testing. The most consistent magnetic resonance imaging abnormality is an increased signal in the globus pallidus. Magnetic resonance spectroscopy has demonstrated the first example of increased endogenous GABA in human brain parenchyma in this disorder. GABA-transaminase deficiency and homocarnosinosis appear to be very rare, but require cerebrospinal fluid for detection, thus allowing for the possibility that these entities, as in the other inherited neurotransmitter disorders, are under-recognized.
γ-amino butyric acid; γ-hydroxybutyrate; homocarnosine; seizures; succinic semialdehyde dehydrogenase; vigabatrin
In Alzheimer's disease, the key pathological culprit is the amyloid-β protein, which is generated through β- and γ-secretase cleavage of the amyloid-β precursor protein (APP). Both the secretases and amyloid-β precursor protein are transmembrane proteins that are sorted via the trans-Golgi network and the endosome through multiple membranous compartments of the cell. The coat complex clathrin controls the sorting from the cell surface and the trans-Golgi network to the endosome. Instead, the retromer controls the reverse transport from the endosome to the trans-Golgi network. The retromer contains two subprotein complexes: the cargo-selective subcomplex consisting of VPS35, VPS29 and VPS26 and the membrane deformation subcomplex consisting of Vps5p, Vps17p, SNX 1/2 and possibly SNX 5/6 or SNX 32 in mammals. Cargo molecules of the retromer include the VPS10 receptor proteins SORL1, SORT1, SORCS1, SORCS2 and SORCS3. There is increasing evidence through cell biology and animal and genetic studies that components of the retromer and the VPS10d receptor family play a role in the etiology of Alzheimer's disease. This article reviews and summarizes this current evidence.
Alzheimer's disease; amyloid; APP processing; intracellular trafficking; retromer; VPS10d receptors
Stem cell therapy for adult stroke has reached limited clinical trials. Here, we provide translational research guidance on stem cell therapy for neonatal hypoxic-ischemic brain injury requiring a careful consideration of clinically relevant animal models, feasible stem cell sources, and validated safety and efficacy endpoint assays, as well as a general understanding of modes of action of this cellular therapy. To this end, we refer to existing translational guidelines, in particular the recommendations outlined in the consortium of academicians, industry partners and regulators called Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS. Although the STEPS guidelines are directed at enhancing the successful outcome of cell therapy in adult stroke, we highlight overlapping pathologies between adult stroke and neonatal hypoxic-ischemic brain injury. We are, however, cognizant that the neonatal hypoxic-ischemic brain injury displays disease symptoms distinct from adult stroke in need of an innovative translational approach that facilitates the entry of cell therapy in the clinic. Finally, insights into combination therapy are provided with the vision that stem cell therapy may benefit from available treatments, such as hypothermia, already being tested in children diagnosed with hypoxic-ischemic brain injury.
cerebral palsy; stem cells; hypothermia; neurorestoration; translational; consortium; combination therapy
Dynamic changes in neuroinflammation and glutamate NMDA receptors (NMDAR) have been noted in traumatic and ischemic brain injury.
Here we investigate the time course and regional distribution of these changes and their relationship with atrophy in a rat model of penetrating brain injury.
Materials & methods
Quantitative autoradiography, with the neuroinflammation marker [3H]PK11195 and the NMDAR antagonist [125I]iodoMK801, was performed on brains of animals subjected to a unilateral wireknife injury at the level of striatum and killed 3 – 60 days later. Regional atrophy was measured by morphometry.
The injury produced large increases in [3H]PK11195 binding density in cortical and septal regions adjacent to the knife track by day 7, with modest increases in the striatum. [125I]iodoMK801 binding was reduced in cor tical and hippocampal regions showing marked neuroinflammation, which showed marked atrophy at subsequent time points.
These results indicate that neuroinflammaton and loss of NMDAR precede and predict tissue atrophy in cortical and hippocampal regions.
brain atrophy; brain injury; neuroinflammation; NMDA receptors; peripheral benzodiazepine receptors; TSPO
Getting gray hair is part of the natural progression of aging. People expect it and they can change their hair color, if they choose. People also expect increases in memory lapses and learning difficulties as they get older. However, unlike hair color, there is no magic cure or option to fix learning and memory difficulties, because the cellular mechanisms of learning and aging in all the different types of neurons throughout the brain have yet to be discovered. This review describes our efforts to identify a cellular biomarker in hippocampal pyramidal neurons that has been demonstrated to reliably change with learning and with aging – the postburst afterhyperpolarization. We propose that this biomarker, which plays a critical role in regulating neuronal excitability, can be used as a benchmark for future studies in order to understand and identify the cellular mechanisms of learning and aging in the hippocampus, as well as in other cortical regions.
calcium channels; eyeblink conditioning; Henry Gustav Molaison; hippocampus; postburst afterhyperpolarization
Alzheimer’s disease (AD) exhibits a complex etiology that simultaneously manifests as a complex cellular, neurobiological, molecular, anatomic–physiological and clinical entity. Other significant psychiatric conditions, such as depression and schizophrenia, may also present with complex and concurrent clinical and/or molecular phenotypes. These neuropsychiatric pathologies also originate from both environmental and genetic factors. We analyzed the molecular phenotypes of AD and discuss them with respect to the classical theories, which we integrated into mechanisms that share molecular and/or anatomical connections. Based on these mechanisms, we propose an interaction model and discuss the model in light of studies that refute or support it. Given the spectrum of AD phenotypes, we limit the scope of our discussion to a few, which facilitates concrete analysis. In addition, the study of specific, individual pathogenic phenotypes may be critical to defining the complex mechanisms leading to AD, thereby improving strategies for developing novel therapies.
Alzheimer’s disease; amyloid-β; apolipoprotein E; neurofibrillary tangles; Parkinson’s disease; reactive oxygen species
CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated functions subserved by this protein. Together with its canonical roles in neurite growth and retraction and kinesin-dependent axonal transport, it is now known that CRMP2 interacts with numerous binding partners to affect microtubule dynamics; protein endocytosis and vesicular cycling, synaptic assembly, calcium channel regulation and neurotransmitter release. CRMP2 signaling is regulated by post-translational modifications, including glycosylation, oxidation, proteolysis and phosphorylation; the latter being a fulcrum of CRMP2 functions. Here, the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders are discussed and evidence is presented for therapeutic strategies targeting CRMP2 functions.
Alzheimer’s disease; amyotrophic lateral sclerosis; axon elongation; CRMP2; CRMP2/CLN6/KLC4 signaling complex; CRMP2 hyperphosphorylation; excitotoxicity; multiple sclerosis; neuropathic pain; oxidative damage
Neurodegenerative disorders lead to disability and death in a significant proportion of the world’s population. However, many disorders of the nervous system remain with limited effective treatments. Kinase pathways in the nervous system that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR) offer exciting prospects for the understanding of neurodegenerative pathways and the development of new avenues of treatment. PI 3-K, Akt, and mTOR pathways are vital cellular components that determine cell fate during acute and chronic disorders, such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, epilepsy, stroke, and trauma. Yet, the elaborate relationship among these kinases and the variable control of apoptosis and autophagy can lead to unanticipated biological and clinical outcomes. Crucial for the successful translation of PI 3-K, Akt, and mTOR into robust and safe clinical strategies will be the further elucidation of the complex roles that these kinase pathways hold in the nervous system.
Akt; apoptosis; Alzheimer’s disease; autophagy; Huntington’s disease; mammalian target of rapamycin (mTOR); Parkinson’s disease; phosphoinositide 3–kinase (PI 3-K); stroke; trauma
Accumulation of senile plaques consisting of amyloid-β peptide (Aβ) aggregates is a prominent pathological feature in Alzheimer’s disease. Effective clearance of Aβ from the brain parenchyma is thought to regulate the development and progression of the disease. Macrophages in the brain play an important role in Aβ clearance by a variety of phagocytic and digestive mechanisms. Subpopulations of macrophages are heterogeneous such that resident microglia in the parenchyma, blood macrophages infiltrating from the periphery, and perivascular macrophages residing along cerebral vessels make functionally distinct contributions to Aβ clearance. Despite phenotypic similarities between the different macrophage subsets, a series of in vivo models have been derived to differentiate their relative impacts on Aβ dynamics as well as the molecular mechanisms underlying their activities. This review discusses the key findings from these models and recent research efforts to selectively enhance macrophage clearance of Aβ.
PMID: 22737039 CAMSID: cams2215
Alzheimer’s disease; a myloid- β peptide; microglia; macrophages; perivascular macrophages; phagocytosis
Alzheimer’s disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy.
amyloid precursor protein; dentate gyrus; hilus; mossy fiber sprouting; neurodegeneration; presenilin-1; seizure; temporal lobe
Of the various genetic factors contributing to the pathogenesis of Parkinson’s disease (PD), only mutations in α-synuclein (α-syn) and LRRK2 genes cause clinical and neuropathological phenotypes closely resembling the sporadic cases. Therefore, studying the pathophysiological functions of these two PD-related genes is particularly informative in understanding the underlying molecular pathogenic mechanism of the disease. PD-related missense and multiplication mutations in α-syn may cause both early- and late-onset PD, whereas various PD-related LRRK2 missense mutations may contribute to the more common late-onset PD. While intensive studies have been carried out to elucidate the pathogenic properties of PD-related mutant α-syn and LRRK2, our knowledge of their normal functions and their potential genetic interplay remains rudimental. In this review, we summarize the progress made regarding the pathophysiological functions of α-syn, LRRK2 and their interaction in PD, based on the available literature and our unpublished observations.
14-3-3; α-synuclein; actin; autophagy; ER; Golgi apparatus; leucine-rich repeat kinase 2; Lewy body; microtubule; mitochondria; Parkinson’s disease; proteasome
Reprogramming of somatic cells to an embryonic-like state has dramatically changed the landscape of stem cell research. Although still in its formative stages, the field of induced pluripotent stem cells (iPSCs) has the potential to advance the study of neurodegenerative and neurodevelopmental disorders at the molecular and cellular levels. The iPSC technology could be employed to establish in vitro experimental model systems for the identification of molecular lesions and to aid in the discovery of therapeutic targets and effective compounds. The derivation of patient-specific iPSCs has also opened up the possibility of generating disease-relevant cells for toxicity screening and for cellular therapy. In this article, we review the recent progress in the use of disease-specific iPSCs for in vitro and in vivo modeling of neurological diseases.
disease modeling; human induced pluripotent stem cell; neurobiology; neurodegenerative; neurodevelopmental
Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized.
brain development; cannabinoid receptor; cannabis; cortex; endocannabinoids; THC
Congenital CNS abnormalities have been targets for prenatal intervention since the founding of fetal surgery 30 years ago, but with historically variable results. Open fetal neurosurgery for myelomenigocele has demonstrated the most promising results of any CNS malformation. Improvements in the understanding of congenital diseases and in fetal surgical techniques have reopened the door to applying fetal surgery to other congenital CNS abnormalities. Advances in gene therapy, bioengineering and neonatal neuroprotection will aid in the future expansion of fetal neurosurgery to other CNS disorders.
congenital neurodegenerative disorder; fetal neurosurgery; fetal surgery; gene therapy; hydrocephalus; myelomeningocele; spina bifida; stem cell
Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke.
This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke.
Materials & methods
Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison.
DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy.
These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.
cognition; d-cycloserine; fMRI; infarction; NMDA receptor; stroke