The inflammation hypothesis of Alzheimer’s pathogenesis has directed much scientific effort towards ameliorating this disease. The development of mouse models of amyloid deposition permitted direct tests of the proposal that amyloid-activated microglia could cause neurodegeneration in vivo. Many approaches to manipulating microglial activation have been applied to these mouse models, and are the subject of this review. In general, these results do not support a direct neuricidal action of microglia in mouse amyloid models under any activation state. Some of the manipulations cause both a reduction in pathology, and a reduction in microglial activation. However, at least for agents like ibuprofen, this outcome may result from a direct action on amyloid production, and a reduction in the microglial provoking amyloid deposits, rather than from reduced microglial activation leading to a decline in amyloid deposition. Instead, a surprising number of the experimental manipulations which increase microglial activation lead to enhanced clearance of the amyloid deposits. Both the literature and new data presented here suggest that either classical or alternative activation of microglia can lead to enhanced amyloid clearance. However, a limited number of studies comparing the same treatments in amyloid-depositing vs tau-depositing mice find the opposite effects. Treatments that benefit amyloid pathology accelerate tau pathology. This observation argues strongly that potential treatments be tested for impact on both amyloid and tau pathology before consideration of testing in humans.
cytokines; chemokines; neuroimmunology; tauopathy; inflammation; toll-like receptors; complement; nonsteroidal anti-inflammatory drugs (NSAIDs)
Abnormalities of the hippocampus are associated with a range of diseases in children, including
epilepsy and sudden death. A population of rod cells in part of the hippocampus, the polymorphic
layer of the dentate gyrus, has long been recognized in infants. Previous work suggested that these
cells were microglia and that their presence was associated with chronic illness and sudden infant
death syndrome. Prompted by the observations that a sensitive immunohistochemical marker of
microglia used in diagnostic practice does not typically stain these cells and that the hippocampus
is a site of postnatal neurogenesis, we hypothesized that this transient population of cells were
not microglia but neural progenitors.
Using archived post mortem tissue, we applied a broad panel of antibodies to
establish the immunophenotype of these cells in 40 infants dying suddenly of causes that were either
explained or remained unexplained, following post mortem investigation.
The rod cells were consistently negative for the microglial markers CD45, CD68 and HLA-DR. The
cells were positive, in varying proportions, for the neural progenitor marker, doublecortin, the
neural stem cell marker, nestin and the neural marker, TUJ1.
These data support our hypothesis that the rod cells of the polymorphic layer of the dentate
gyrus in the infant hippocampus are not microglia but a population of neural progenitors. These
findings advance our understanding of postnatal neurogenesis in the human hippocampus in health and
disease and are of diagnostic importance, allowing reactive microglia to be distinguished from the
normal population of neural progenitors.
dentate gyrus; doublecortin; hippocampus; neural progenitor; polymorphic layer
Traumatic brain injury is a significant cause of morbidity and mortality worldwide. An epidemiological association between head injury and long-term cognitive decline has been described for many years and recent clinical studies have highlighted functional impairment within 12 months of a mild head injury. In addition chronic traumatic encephalopathy is a recently described condition in cases of repetitive head injury. There are shared mechanisms between traumatic brain injury and Alzheimer’s disease, and it has been hypothesised that neuroinflammation, in the form of microglial activation, may be a mechanism underlying chronic neurodegenerative processes after traumatic brain injury.
This study assessed the microglial reaction after head injury in a range of ages and survival periods, from <24 hours survival through to 47 years survival. Immunohistochemistry for reactive microglia (CD68 and CR3/43) was performed on human autopsy brain tissue and assessed “blind” by quantitative image analysis. Head injury cases were compared to age matched controls, and within the traumatic brain injury group cases with diffuse traumatic axonal injury were compared to cases without diffuse traumatic axonal injury.
A major finding was a neuroinflammatory response which develops within the first week and persists for several months after TBI, but has returned to control levels after several years. In cases with diffuse traumatic axonal injury the microglial reaction is particularly pronounced in the white matter.
These results demonstrate that prolonged microglial activation is a feature of traumatic brain injury, but that the neuroinflammatory response returns to control levels after several years.
neurotrauma; microglia; neuroinflammation; traumatic axonal injury
To determine whether testing for isolated 1p or 19q losses, or as a codeletion, has any significance in the workup of glioblastomas (GBMs).
Upfront 1p/19q testing by fluorescence in situ hybridization (FISH) and/or polymerase chain reaction (PCR)-based loss of heterozygosity (LOH) was done in 491 gliomas that were histologically diagnosed as GBMs. Outcomes were determined and measured against 1p/19q results.
Twenty-eight showed apparent 1p/19q codeletion by either FISH and/or PCR-based LOH, but only 1/26 showed codeletion by both tests. Over 90% of tumours with apparent codeletion by either FISH or LOH also had 10q LOH and/or EGFR amplification, features inversely related to true whole-arm 1p/19q codeletion. Furthermore, only 1/28 tumours demonstrated an R132H IDH1 mutation. Neither 1p/19q codeletion by FISH nor LOH had an impact on GBM survival. Isolated losses of 1p or 19q also had no impact on survival.
These data suggest that (i) 1p/19q testing is not useful on gliomas that are histologically GBMs; (ii) codeletion testing should be reserved only for cases with compatible morphology; and (iii) EGFR, 10q, and IDH1 testing can help act as safeguards against a false-positive 1p/19q result.
1p/19q; FISH; glioblastoma; LOH
Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid β protein (Aβ) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer’s disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a one-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva.
Materials and methods
Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal, and occipital cortex, using an antibody against Aβ, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established.
CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age, followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters.
The present data show that CAA plays a role in the development of microvascular lesions in the aging brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contributes importantly to the pathogenesis of microvascular changes.
amyloid angiopathy; cortical microinfarcts; Alzheimer’s disease; vascular; neuropathology; immunohistochemistry
The classification of malignant gliomas is moving from a morphology-based guide to a system built on molecular criteria. The development of a genomic landscape for gliomas and a better understanding of its functional consequences have led to the development of internally consistent molecular classifiers. However, development of a biologically insightful classification to guide therapy is still a work in progress. Response to targeted treatments is based not only on the presence of drugable targets, but rather on the molecular circuitry of the cells. Further, tumours are heterogeneous and change and adapt in response to drugs. Therefore, the challenge of developing molecular classifiers that provide meaningful ways to stratify patients for therapy remains a major challenge for the field. In this review, we examine the potential role of MGMT methylation, IDH1/2 mutations, 1p/19q deletions, aberrant epidermal growth factor receptor and PI3K pathways, abnormal p53/Rb pathways, cancer stem-cell markers and microRNAs as prognostic and predictive molecular markers in the setting of adult high-grade gliomas and we outline the clinically relevant subtypes of glioblastoma with genomic, transcriptomic and proteomic integrated analyses. Furthermore, we describe how these advances, especially in epidermal growth factor receptor/PI3K/mTOR signalling pathway, affect our approaches towards targeted therapy, raising new challenges and identifying new leads.
high-grade gliomas; integrated analyses; molecular markers; predictive factors; prognostic factors; target therapies
Previous data suggest heterogeneity in laminar distribution of the pathology in the molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP). To study this heterogeneity, we quantified the changes in density across the cortical laminae of neuronal cytoplasmic inclusions (NCI), glial inclusions (GI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN), surviving neurons, abnormally enlarged neurons (EN), and vacuoles in regions of the frontal and temporal lobe.
Changes in density of histological features across cortical gyri were studied in ten sporadic cases of FTLD-TDP using quantitative methods and polynomial curve-fitting.
Our data suggest that laminar neuropathology in sporadic FTLD-TDP is highly variable. Most commonly, NCI, DN, and vacuolation were abundant in the upper laminae and GI, NII, EN, and glial cell nuclei in the lower laminae. TDP-43-immunoreactive inclusions affected more of the cortical profile in longer duration cases, their distribution varied with disease subtype, but was unrelated to Braak tangle score. Different TDP-43-immunoreactive inclusions were not spatially correlated.
Laminar distribution of pathological features in ten sporadic cases of FTLD-TDL is heterogeneous and may be accounted for, in part, by disease subtype and disease duration. In addition, the feed-forward and feed-back cortico-cortical connections may be compromised in FTLD-TDP.
Frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP); FTLD with ubiquitin-positive inclusions (FTLD-U); Transactive response TAR DNA-binding protein of 43 kDa (TDP-43); Neuronal cytoplasmic inclusions (NCI); Laminar distribution
The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data however are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development.
We investigated the dorsal anterior cingulate cortex (dACC) in 13 males with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neuron and glial numbers, and glia/neuron (GNI) ratios in both layers II-III and V-VI.
We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neuron numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development.
Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post-mortem histopathological studies and in vivo brain imaging findings in patients.
dysmyelination; oligodendrocytes; white matter; morphology; cytoarchitecture; myelin
Myotonic dystrophy types 1 and 2 (DM1 and DM2) are multisystem disorders caused by similar repeat expansion mutations, with similar yet distinct clinical features. Aberrant splicing of multiple effector genes, as well as dysregulation of transcription and translation, have been suggested to underlie different aspects of the complex phenotypes in DM1 and DM2. Ca2+ plays a central role in both muscle contraction and control of gene expression, and recent expression profiling studies have indicated major perturbations of the Ca2+ signaling pathways in DM. Here we have further investigated the expression of genes and proteins involved in Ca2+ metabolism in DM patients, including Ca2+ channels and Ca2+ binding proteins.
We used patient muscle biopsies to analyze mRNA expression and splicing of genes by microarray expression profiling and RT-PCR. We studied protein expression by immunohistochemistry and immunoblotting.
Most of the genes studied showed mRNA up-regulation in expression profiling. When analyzed by immunohistochemistry the Ca2+ release channel ryanodine receptor was reduced in DM1 and DM2, as was calsequestrin 2, a sarcoplasmic reticulum lumen Ca2+ storage protein. Abnormal splicing of ATP2A1 was more pronounced in DM2 than DM1.
We observed abnormal mRNA and protein expression in DM affecting several proteins involved in Ca2+ metabolism, with some differences between DM1 and DM2. Our protein expression studies are suggestive of a post-transcriptional defect(s) in the myotonic dystrophies.
Myotonic dystrophy type 1 (DM1); myotonic dystrophy type 2 (DM2); skeletal muscle; calcium metabolism
Prion diseases are characterized by brain deposits of misfolded aggregated protease-resistant prion protein (PrP), termed PrPres. In humans and animals, PrPres is found as either disorganized non-amyloid aggregates or organized amyloid fibrils. Both PrPres forms are found in extracellular spaces of the brain. Thus, both might block drainage of brain interstitial fluid (ISF). The present experiments studied whether ISF blockage occurred during amyloid and/or non-amyloid prion diseases.
Various-sized fluorescein-labeled ISF tracers were stereotactically inoculated into the striatum of adult mice. At times from 5 min to 77 hours, uninfected and scrapie-infected mice were compared. C57BL/10 mice expressing wild-type anchored PrP, which develop non-amyloid PrPres similar to humans with sporadic CJD, were compared with Tg44+/+ mice expressing anchorless PrP, which develop amyloid PrPres similar to certain human familial prion diseases.
In C57BL/10 mice, extensive non-amyloid PrPres aggregate deposition was not associated with abnormal clearance kinetics of tracers. In contrast, scrapie-infected Tg44+/+ mice showed blockage of tracer clearance and co-localization of tracer with perivascular PrPres amyloid.
Since tracer localization and clearance was normal in infected C57BL/10 mice, ISF blockage was not an important pathogenic mechanism in this model. Therefore, ISF blockage is unlikely to be a problem in non-amyloid human prion diseases such as sporadic CJD. In contrast, partial ISF blockage appeared to be a possible pathogenic mechanism in Tg44+/+ mice. Thus this mechanism might also influence human amyloid prion diseases where expression of anchorless or mutated PrP results in perivascular amyloid PrPres deposition and cerebral amyloid angiopathy (CAA).
brain interstitial fluid; cerebral amyloid angiopathy; prion; glycophosphatidylinositol anchor; basement membrane
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelination of white matter, loss of myelin forming oligodendrocytes, changes in the blood-brain-barrier (BBB), and leukocyte infiltration. Myelin basic protein (MBP) is a component of the myelin sheath. Degradation of myelin is believed to be an important step that leads to MS pathology. Transmigration of leukocytes across the vasculature, and a compromised BBB participate in the neuroinflammation of MS. We examined the expression and regulation of the chemokine CCL2 and the cytokine IL-6 in human endothelial cells (EC), a component of the BBB, after treatment with MBP.
EC were treated with full length MBP. CCL2 and IL-6 protein were determined by ELISA. Western blot analysis was used to determine signaling pathways. A BBB model was treated with MBP and permeability was assayed using albumin conjugated to Evan’s blue dye. The levels of the tight junction proteins occludin and claudin-1, and matrix metalloprotease (MMP)-2 were assayed by Western blot.
MBP significantly induced CCL2 and IL-6 protein from EC. This induction was partially mediated by the p38 MAPK pathway as there was phosphorylation after MBP treatment. MBP treatment of a BBB model caused an increase in permeability that correlated with a decrease in occludin and claudin-1, and an induction of MMP-2.
These data demonstrate that MBP induces chemotactic and inflammatory mediators. MBP also alters BBB permeability and tight junction expression, indicating additional factors that may contribute to the BBB breakdown characteristic of MS.
MBP; MMP2; IL-6; CCL2; EAE; blood-brain-barrier; MS
Innate immunity within the central nervous system (CNS) is primarily provided by resident microglia. Microglia are pivotal in immune surveillance and also facilitate the coordinated responses between the immune system and the brain. For example, microglia interpret and propagate inflammatory signals that are initiated in the periphery. This transient microglial activation helps mount the appropriate physiological and behavioral response following peripheral infection. With normal aging, however, microglia develop a more inflammatory phenotype. For instance, in several models of aging there are increased pro-inflammatory cytokines in the brain and increased expression of inflammatory receptors on microglia. This increased inflammatory status of microglia with aging is referred to as primed, reactive, or sensitized. A modest increase in the inflammatory profile of the CNS and altered microglial function in aging has behavioral and cognitive consequences. Nonetheless, there are major differences in microglial biology between young and old age when the immune system is challenged and microglia are activated. In this context, microglial activation is amplified and prolonged in the aged brain compared to adults. The cause of this amplified microglial activation may be related to impairments in several key regulatory systems with age that make it more difficult to resolve microglial activation. The consequences of impaired regulation and microglial hyper-activation following immune challenge are exaggerated neuroinflammation, sickness behavior, depressive-like behavior and cognitive deficits. Therefore the purpose of this review is to discuss the current understanding of age-associated microglial priming, consequences of priming and reactivity, and the impairments in regulatory systems that may underlie these age-related deficits.
Brain; Microglia; Aging; Inflammation; Behavior
Microglia cells have been implicated, to some extent, in the pathogenesis of all of the common neurodegenerative disorders involving protein aggregation such as Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. However, the precise role they play in the development of the pathologies remains unclear and it seems that they contribute to the pathological process in different ways depending on the specific disorder. A better understanding of their varied roles is essential if they are to be the target for novel therapeutic strategies.
Microglia; protein aggregates neuroinflammation; cytokines; neurotoxicity; Alzheimer’s; Parkinson’s; ALS
Activated microglia overexpressing interleukin-1 (IL-1) are prominent neuropathological features of Alzheimer’s disease. We used computerized image analysis to determine the number of IL-1α-immunoreactive (IL-1α+) microglia in cytoarchitectonic layers of parahippocampal gyrus (Brodmann’s area 28) of Alzheimer and control patients. For cortical layers I and II, the numbers of IL-1α+ microglia were similar in Alzheimer and control patients. For layers III–VI, the numbers of IL-1α+ microglia were higher than that seen in layers I–II for both Alzheimer and control patients. Moreover, for layers III–VI, the number of IL-1α+ microglia in Alzheimer patients was significantly greater than that in control patients (relative Alzheimer values of threefold for layer III–V and twofold for layer VI; P<0.05 in each case). The cortical laminar distribution of IL-1α+ microglia in Alzheimer patients correlated with the cortical laminar distribution of β-amyloid precursor protein-immunoreactive (β-APP+) neuritic plaques found in Alzheimer patients (r=0.99, P<0.005). Moreover, the cortical laminar distribution of IL-1α+ microglia in control patients also correlated with the cortical laminar distribution of β-APP+ neuritic plaques found in Alzheimer patients (r=0.91, P<0.05). These correlations suggest that pre-existing laminar distribution patterns of IL-1α+ microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of β-APP+ neuritic plaques in Alzheimer patients. These findings provide further support for our hypothesis that IL-1 is a key driving force in neuritic plaque formation in Alzheimer’s disease.
Alzheimer’s disease; β-amyloid precursor protein; cerebral cortical layers; interleukin-1; microglia
We aimed to investigate the role of the nuclear carrier and binding proteins, transportin-1 (TRN1) and transportin-2 (TRN2), TATA-binding protein-associated factor 15 (TAF15) and Ewing’s Sarcoma protein (EWS) in inclusion body formation in cases of Frontotemporal Lobar Degeneration (FTLD) associated with Fused in Sarcoma protein (FTLD-FUS).
Eight cases of FTLD-FUS (5 cases of atypical FTLD-U (aFTLD-U), 2 of Neuronal Intermediate Filament Inclusion Body Disease (NIFID) and 1 of Basophilic Inclusion Body Disease (BIBD)) were immunostained for FUS, TRN1, TRN2, TAF15 and EWS. 10 cases of FTLD associated with TDP-43 inclusions served as reference cases.
The inclusion bodies in FTLD-FUS contained TRN1 and TAF15 and, to a lesser extent, EWS, but not TRN2. The patterns of immunostaining for TRN1 and TAF15 were very similar to that of FUS. None of these proteins was associated with tau or TDP-43 aggregations in FTLD.
Data suggest that FUS, TRN1 and TAF15 may participate in a functional pathway in an interdependent way, and imply that the function of TDP-43 may not necessarily be in parallel with, or complementary to, that of FUS, despite each protein sharing many similar structural elements.
Frontotemporal Lobar degeneration; Fused in Sarcoma; TDP-43; transportins; TATA-binding protein-associated factor 15; Ewing’s sarcoma protein
Many variables affect mRNA measurements in post mortem human brain tissue. Brain weight has not hitherto been considered to be such a factor. This study investigated whether there is any relationship between brain weight and mRNA abundance.
We investigated quantitative real-time RT-PCR data for five ‘housekeeping genes’ using the 104 adult brains of the Stanley Microarray Consortium series. Eleven datasets were analysed, from cerebellum, hippocampus, and anterior cingulate cortex. We used a specified sequence of correlations, partial correlations, and multiple regression analyses.
Brain weight correlated with the ‘raw’ (i.e. non-normalised) data for two mRNAs, β2-microglobulin (β2M) and TATA-binding protein (TBP), measured in cerebellum and hippocampus respectively. In hippocampus, the geometric mean of three housekeeping gene transcripts also correlated with brain weight. The correlations were significant after adjusting for age, sex and other confounders, and the effect of brain weight was confirmed using multiple regression. No correlations with brain weight were seen in the anterior cingulate cortex, nor for the other mRNAs examined.
The findings were not anticipated; they need replication in another brain series, and a more systematic survey is indicated. In the interim, we suggest that quantitative gene expression studies in human brain should inspect for a potential influence of brain weight, especially since the affected transcripts are commonly used as reference genes for normalisation purposes in studies of neurological and psychiatric disorders. The relationship of brain weight with β2M mRNA may reflect the roles of MHC class I genes in synapse formation and plasticity.
Brain size; Gene expression; Messenger RNA; Schizophrenia, Real-time PCR
The pathology of Alzheimers's disease (AD) is characterized by the presence of amyloid plaques (APs), neurofibrillary tangles (NFTs), degenerating neurons, and an abundance of reactive astrocytes and microglia. We aim to examine the association between glia maturation factor (GMF) expression, activated astrocytes/microglia, APs, and NFTs in AD affected brain regions.
Brain sections were stained with Thioflavin-S to study AD pathology and sequentially immunolabeled with antibodies against GMF, glial fibrillary acidic protein (GFAP, marker for reactive astrocytes), and Ionized calcium binding adaptor molecule 1 (Iba1, marker for activated microglia) followed by visualization with avidin-biotin peroxidase complex.
Our double immunofluorescence labeling with cell-specific markers demonstrated the glial localization of GMF. The immunohistochemical data showed that APs and NFTs are associated with increased expression of GMF in reactive glia of AD brains compared to non-AD controls.
This is the first report that shows GMF, a mediator of CNS inflammation, is expressed in the brain regions affected in AD and that GMF is mainly localized in reactive astrocytes surrounding APs/NFTs. The distribution of GMF-immunoreactive cells in and around Thioflavin-S stained APs and NFTs suggests involvement of GMF in inflammatory responses through reactive glia and a role of GMF in AD pathology.
Glia maturation factor (GMF); Alzheimer's disease (AD); Neuropathology; Neuroinflammation; Reactive glia; Amyloid plaques (APs); Neurofibrillary tangles (NFTs); Tau-protein
Combined anti-retroviral therapy (cART) has led to a reduction in the incidence of HIV-associated dementia (HAD), a severe motor/cognitive disorder afflicting HIV(+) patients. However, the prevalence of subtler forms of neurocognitive dysfunction, which together with HAD are termed HIV-associated neurocognitive disorders (HAND), continues to escalate in the post-cART era. The microgliosis, astrogliosis, dendritic damage, and synaptic and neuronal loss observed in autopsy cases suggest an underlying neuroinflammatory process, due to the neurotoxic factors released by HIV-infected/activated macrophages/ microglia in the brain, might underlie the pathogenesis of HAND in the post-cART era. These factors are known to induce the integrated stress response (ISR) in several neurodegenerative diseases; we have previously shown that BiP, an indicator of general ISR activation, is upregulated in cortical autopsy tissue from HIV-infected patients. The ISR is composed of three pathways, each with its own initiator protein: PERK, IRE1α and ATF6.
To further elucidate the specific ISR pathways activated in the central nervous system of HAND patients, we examined the protein levels of several ISR proteins, including ATF6, peIF2α and ATF4, in cortical tissue from HIV-infected patients.
The ISR does not respond in an all-or-none fashion in HAND, but rather demonstrates a nuanced activation pattern. Specifically, our studies implicate the ATF6 pathway of the ISR as a more likely candidate than the PERK pathway for increases in BiP levels in astrocytes.
These findings begin to characterize the nature of the ISR response in HAND and provide potential targets for therapeutic intervention in this disease.
astrocyte; ATF6; ER stress response; HAND; HIV; neurone
High grade gliomas (HGG) are devastating primary brain tumors with universally poor prognoses. Advances toward effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumor initiation, progression, and phenotype, the influence of tumor microenviroment, and the analysis of cell types that can give rise to glioma. HGGs are a highly heterogeneous group of tumors, and the complexity of diverse mutations within common signaling pathways as well as the developmental and cell-type context of transformation contribute to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely approximate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing.
Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during REM sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurons in a neighbouring nucleus, the locus coeruleus (LC).
This retrospective study, utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 AD and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurons of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry.
Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD.
Whether decreases in brainstem cholinergic neurons in LBD contribute to RBD is uncertain, but our findings indicate these neurons are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.
α-synuclein; cholinergic; Lewy body; laterodorsal tegmentum; locus coeruleus; pedunculopontine nucleus; REM behaviour disorder; tau
The pathogenesis of HIV/SIV encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood brain barrier. Heretofore, it has not been possible to easily determine if an individual has HIVE/SIVE before post mortem examination.
We have examined serum levels of the astroglial protein S100β in SIV-infected macaques and show that it can be used to determine which animals will have SIVE. We also checked for correlations with inflammatory markers such as CCL2/ MCP-1, IL-6 and C Reactive Protein (CRP).
We also found that increased S100β protein in serum correlated with decreased expression of the tight junction protein zonula occludens-1 on brain microvessels. Further, the decrease in zonula occludens-1 expression was spatially related to SIVE lesions and perivascular deposition of plasma fibrinogen. There was no correlation between encephalitis and plasma levels of IL-6, MCP-1/CCL2 or CRP.
Together these data indicate that SIVE lesions are associated with vascular leakage that can be monitored by S100β protein in the periphery. The ability to simply monitor the development of SIVE will greatly facilitate studies of the neuropathogenesis of AIDS.
Atypical (WHO grade II) meningiomas have moderately high recurrence rates; even for completely resected tumours, approximately one-third will recur. Postoperative radiotherapy (RT) may aid local control and improve survival, but carries the risk of side effects. More accurate prediction of recurrence risk is therefore needed for patients with atypical meningioma. Previously, we used high-resolution array CGH to identify genetic variations in 47 primary atypical meningiomas and found that approximately 60% of tumors show gain of 1q at 1q25.1 and 1q25.3 to 1q32.1 and that 1q gain appeared to correlate with shorter progression-free survival. This study aimed to validate and extend these findings in an independent sample.
86 completely resected atypical meningiomas (with 25 recurrences) from two neurosurgical centres in Ireland were identified and clinical follow up was obtained. Utilizing a dual-colour interphase FISH assay, 1q gain was assessed using BAC probes directed against 1q25.1 and 1q32.1.
The results confirm the high prevalence of 1q gain at these loci in atypical meningiomas. We further show that gain at 1q32.1 and age each correlate with progression-free survival in patients who have undergone complete surgical resection of atypical meningiomas.
These independent findings suggest that assessment of 1q copy number status can add clinically useful information for the management of patients with atypical meningiomas.
meningioma; atypical; pathology; classification; genetics
To further characterize the neuropathology of the heterogeneous molecular disorder frontotemporal lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP).
We quantified the neuronal cytoplasmic inclusions (NCI), glial inclusions (GI), neuronal intranuclear inclusions (NII), dystrophic neurites (DN), surviving neurons, abnormally enlarged neurons (EN), and vacuoles in regions of the frontal and temporal lobe using a phosphorylation independent TDP-43 antibody in thirty-two cases of FTLD-TDP comprising sporadic and familial cases, with associated pathology such as hippocampal sclerosis (HS) or Alzheimer’s disease (AD), and four neuropathological subtypes using TDP-43 immunohistochemistry. Analysis of variance (ANOVA) was used to compare differences between the various groups of cases.
These data from FTLD-TDP cases demonstrate quantitative differences in pathological features between: (1) regions of the frontal and temporal lobe, (2) upper and lower cortex, (3) sporadic and progranulin (GRN) mutation cases, (4) cases with and without AD or HS, and (5) between assigned subtypes.
The data confirm that the dentate gyrus is a major site of neuropathology in FTLD-TDP and that most laminae of the cerebral cortex are affected. GRN mutation cases are quantitatively different from sporadic cases while cases with associated HS and AD have increased densities of dystrophic neurites (DN) and abnormally enlarged neurons (EN) respectively. There is little correlation between the subjective assessment of subtypes and the more objective quantitative data.
Frontotemporal lobar degeneration with transactive response (TAR) DNA-binding protein of 43kDa (TDP-43) proteinopathy (FTLD-TDP); Density; Neuronal cytoplasmic inclusions (NCI); Neuronal intranuclear inclusion (NII)