Reinnervation is needed to rescue muscle when motoneurons die in disease or injury. Embryonic ventral spinal cord cells transplanted into peripheral nerve reinnervate muscle and reduce atrophy but low motoneuron survival may limit motor unit formation. We tested whether transplantation of a purified population of embryonic motoneurons into peripheral nerve (mean ± SE: 146,458 ± 4011 motoneurons) resulted in more motor units and reinnervation than transplantation of a mixed population of ventral spinal cord cells (72,075 ± 12,329 motoneurons). Ten weeks after either kind of transplant, similar numbers of neurons expressed choline acetyl transferase and/or Islet-1. Motoneuron numbers always exceeded the reinnervated motor unit count. Most motor end plates were simple plaques. Reinnervation significantly reduced muscle fiber atrophy. These data show that the number of transplanted motoneurons or motoneuron survival do not limit muscle reinnervation. Incomplete differentiation of motoneurons in nerve and lack of muscle activity may result in immature neuromuscular junctions that limit reinnervation and function.
Axon regeneration; Motoneuron transplantation; Motor unit; Muscle denervation; Muscle reinnervation; Neuromuscular junction
Central nervous system hypomyelination is a feature common to a number of transgenic (Tg) mouse lines that express a variety of unrelated exogenous (i.e. non-CNS) transgenes. In this report we document hypomyelination structurally by immunocytochemistry and functionally in the Tg line MBP-JE, which overexpresses the chemokine CCL2 (MCP-1) within oligodendrocytes targeted by a myelin basic protein (MBP) promoter. Analysis of hypomyelinated optic nerves of Tg mice revealed progressive decrease in oligodendrocyte numbers with age (p < 0.01). Although molecular mechanisms underlying hypomyelination in this and other Tg models remain largely unknown, we present preliminary findings on oligodendrocyte progenitor cell (OPC) cultures in which, although OPC expressed CCR2, the receptor for CCL2, treatment with CCL2 had no significant effect on OPC proliferation, differentiation or apoptosis. We suggest that hypomyelination in the MBP-JE model might not be due to CCL2 expression but rather the result of transcriptional dysfunction related to random insertion of the MBP promoter that disrupts myelinogenesis and leads to oligodendrocytes demise. Because an MBP promoter is a common denominator in most Tg lines displaying hypomyelination, we hypothesize that use of myelin gene sequences in the regulator region of transgenic constructs might underlie this perturbation of myelination in such models.
Apoptosis; Autoimmune demyelination; Chemokine; Multiple sclerosis; Myelination; Oligodendrocyte; Progenitor cells; Transcription; Transgenic mice
Mild traumatic brain injury (mTBI) leads to long-term cognitive and emotional difficulties and behavioral disturbances, but the diagnosis and treatment of mTBI have historically been hampered by a lack of evidence-based correlates of these clinical manifestations. Unlike moderate and severe TBI, mTBI does not show significant tissue lesions or cavities in the cortex. Moreover, neuroimaging by magnetic resonance imaging or computed tomography is usually negative, suggesting that the damage is beyond the resolution of current structure-based scanning technologies. Therefore, we investigated the morphologies of spared neurons in the mouse cortex after mTBI in a controlled cortical impact injury model. Our results indicate that, although mTBI caused only a mild extent of cell death, it led to extensive dendrite degeneration and synapse reduction in the cortex in this model. This study sheds light on the neuropathologic consequences of mTBI in humans and suggests that neurodegeneration may be a novel target for developing diagnostic methods and therapeutic approaches for mTBI.
Dendrite; mTBI; Neural degeneration; Spine; Synapse
Optic pathway gliomas represent a specific subtype of astrocytoma with unique clinicopathologic and biological properties but studies of tumors in the optic nerve proper have been hampered by limited tissue availability. We analyzed optic nerve gliomas of 59 patients (median age 9 years, range = 3 months to 66 years; 33 female; 26 male) using formalin-fixed paraffin embedded material in tissue microarrays. Seven patients had the clinical diagnosis of neurofibromatosis type 1 (NF1). Fluorescence in situ hybridization studies were performed for BRAF, PTEN, CDKN2A (p16), and NF1. Immunohistochemistry was performed for glial fibrillary acidic protein, phospho-ERK and mutant IDH1R132H protein. BRAF duplication was present in 11 (of 15) (73%) evaluable tumors including 1 NF1 patient (1 of 4 tested, 25%). The single tumor lacking BRAF duplication or NF1-association had histologic features of a ganglioglioma. Conversely, heterozygous PTEN deletions were present in 2 (of 25) (8%) evaluable cases, one of which was BRAF-duplicated and the other NF1-associated. CDKN2A and NF1 deletions were absent in all tumors tested. Phospho-ERK immunoreactivity was present in 55 (of 57) (96%) tumors, and was mostly strong and diffuse (80%). Only 1 case (of 53) expressed IDH1R132H. Thus, optic nerve gliomas demonstrated molecular alterations typical of pilocytic astrocytomas, including the universal presence of either BRAF duplication or NF1-association and common MAPK pathway activation, but very rare mutant IDH1 expression.
BRAF; Fluorescence in situ hybridization (FISH); Glioma; MAPK; Neurofibromatosis; Optic nerve; Pilocytic astrocytoma
Recent experimental data in mice have shown that the inwardly rectifying K+ channel Kir4.1 mediates K+ spatial buffering in the hippocampus. Here we used immunohistochemistry to examine the distribution of Kir4.1 in hippocampi from patients with medication refractory temporal lobe epilepsy. The selectivity of the antibody was confirmed in mice with a glial conditional deletion of the gene encoding Kir4.1. These mice showed a complete loss of labeled cells, indicating that Kir4.1 is restricted to glia. In the human cases, Kir4.1 immunoreactivity observed in cells morphological consistent with astrocytes was significantly reduced in 12 patients with hippocampal sclerosis vs. 11 patients without sclerosis and 4 normal autopsy controls. Loss of astrocytic Kir4.1 immunoreactivity was most pronounced around vessels and was restricted to gliotic areas. Loss of Kir4.1 expression was associated with loss of dystrophin and α-syntrophin, but not with loss of β-dystroglycan, suggesting partial disruption of the dystrophin-associated protein complex. The changes identified in patients with hippocampal sclerosis likely interfere with K+ homeostasis and may contribute to the epileptogenicity of the sclerotic hippocampus.
Astrocytes; Aquaporin; Dystroglycan; Dystrophin; Hippocampal sclerosis; KCNJ10; Syntrophin; Temporal lobe epilepsy
In recent years, 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence guidance has been used as a surgical adjunct to improve the extent of resection of gliomas. Exogenous administration of ALA prior to surgery leads to the accumulation of red fluorescent PpIX in tumor tissue that the surgeon can visualize and thereby discriminate between normal and tumor tissue. Selective accumulation of PpIX has been linked to numerous factors, of which blood-brain barrier (BBB) breakdown has been suggested to be a key factor. To test the hypothesis that PpIX concentration (CPpIX) positively correlates with gadolinium (Gd) concentrations (CGd), we performed ex vivo measurements of PpIX and of Gd using Inductively-Coupled Plasma Mass Spectrometry (ICP-MS) the latter as a quantitative biomarker of BBB breakdown; this was corroborated with immunohistochemistry of microvascular density in surgical biopsies of patients undergoing fluorescence guided surgery for glioma .We found positive correlations between CPpIX and CGd (r = 0.58, p < 0.0001), and between CPpIX and microvascular density (r = 0.55, p < 0.0001), suggesting a significant, yet limited association between BBB breakdown and ALA-induced PpIX fluorescence. To our knowledge, this is the first time that Gd measurements by ICP-MS have been used in human gliomas.
5-aminolevulinic acid; Contrast enhancement on magnetic resonance imaging; Fluorescence guided surgery; Gadolinium; Mass spectrometry; Microvascular density; Protoporphyrin IX
Amyloid-β plaques are a key pathological feature of Alzheimer disease (AD), but whether plaque sizes increase or stabilize over the course of AD is unknown. We measured the size distribution of total immunoreactive (10D5-positive) and dense-core (Thioflavine-S-positive) plaques in the temporal neocortex of a large group of AD and plaque-bearing age-matched non-demented subjects to test the hypothesis that amyloid plaques continue to grow along with the progression of the disease. The size of amyloid-β (10D5)-positive plaques did not differ between groups whereas dense-core plaques from the AD group were slightly larger than those in the non-demented group (~25%–30%, p = 0.01). Within the AD group, dense-core plaque size did not independently correlate with duration of clinical disease (from 4 to 21 years, p = 0.68), whereas 10D5-positive plaque size correlated negatively with disease duration (p = 0.01). By contrast, an earlier age of symptom onset strongly predicted a larger postmortem plaque size; this effect was independent of disease duration and the presence of the APOEε4 allele (p = 0.0001). We conclude that plaques vary in size among patients, with larger size distributions correlating with an earlier age of onset, but plaques do not substantially increase in size over the clinical course of the disease.
Alzheimer disease; Amyloid plaques; APOE genotype; Dense-core plaques; Plaque growth; Plaque size
Human high-grade gliomas (HGGs) are known for their histologic diversity. To address the role of cell of origin in glioma phenotype, transgenic mice were generated in which oncogenic Ras and p53 deletion were targeted to neural stem/progenitor cells (NSPCs) as well as mature astrocytes. hGFAP-Cre/KrasG12D/p53fl/fl mice develop multifocal HGG that vary histopathologically and with respect to the expression of markers associated with NSPCs. One HGG pattern strongly expressed markers of NSPCs and arose near the subventricular zone. Additional, non-overlapping patterns that recapitulate human HGG variants were present simultaneously in the same brain. These neoplastic foci were more often cortical- or leptomeningeal-based and the neoplastic cells lacked expression of NSPC markers. To determine whether cell of origin determines tumor phenotype, astrocytes and NSPCs were harvested from neonatal mutant pups. Upon orthotopic transplantation, early-passage astrocytes and NSPCs formed tumors that differed in engraftment rates, latency to clinical signs, histopathology and protein expression. Astrocyte-derived tumors were more aggressive had giant cell histology and glial fibrillary acidic protein expression. NSPC-derived tumors retained NSPC markers and showed evidence of differentiation along astrocytic, oligodendroglial, and neuronal lineages. These results indicate that identical tumorigenic stimuli produce markedly different glioma phenotypes depending on the differentiation status of the transformed cell.
GFAP-Cre; Glioma; High-grade glioma; Kras; Neural stem/progenitor cells; p53; Transgenic mice
It has long been assumed that β-amyloid (Aβ) had to assemble into fibrillar amyloid plaques to exert its neurotoxic effects in Alzheimer disease. An alternative hypothesis is that soluble oligomers of Aβ play a much larger role in neuronal damage than the insoluble component. We have tested these competing hypotheses in vivo by studying the clinicopathologic correlates of oligomeric Aβ species and classic fibrillar amyloid plaques in the brains of double-transgenic APPsw-tauvlw mice up to 17 months of age. Biochemical and immunohistochemical measures of brain oligomeric Aβ exponentially increased with age. Oligomeric Aβ load correlated with morphological markers of fibrillar Aβ deposition. In contrast to total amyloid plaque burden, the amount of oligomeric Aβ deposits labeled by the con-formational epitope-specific antibody Nab61 closely correlated with neuronal loss and numbers of astrocytes in the entorhinal cortex and the CA1 hippocampal subfield. However, like other morphological Aβ measurements, brain oligomeric Aβ burden did not correlate well with memory deficits in these mice. The number of glial fibrillary acidic protein–positive astrocytes in entorhinal cortex and CA1 most tightly correlated with memory impairment and neuronal cell loss. Based on these findings, we hypothesize that the astrocyte response, which is likely triggered by brain oligomeric Aβ accumulation, adversely affects cognition and might also contribute to neuronal cell death in this model.
Alzheimer disease; Amyloid plaques; Astrocytes; Neuronal cell death; Oligomeric Aβ; Transgenic mice
Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We employed a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation.
Bone morphogenetic protein (BMP); Intrauterine growth retardation; Myelin; Oligodendrocytes; Oxidative stress; Periventricular white matter injury
Brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B (TrkB) may influence brain reserve, the ability of the brain to tolerate pathological changes without significant decline in function. Here, we explore whether a specifically vulnerable population of human neurons shows a compensatory response to the neuropathological changes of Alzheimer disease (AD) and whether that response depends on an upregulation of the BDNF pathway. We observed increased neuronal TrkB expression associated with early AD pathology (Braak and Braak stages I–II) in hippocampal CA1 region samples from cognitively intact Framingham Heart Study subjects (n = 5) when compared to cognitively intact individuals with no neurofibrillary tangles (n = 4). Because BDNF/TrkB signaling affects memory formation and retention through modification of the actin cytoskeleton, we examined the expression of actin capping protein β2 (Capzb2), a marker of actin cytoskeleton reorganization. Capzb2 expression was also significantly increased in CA1 hippocampal neurons of cognitively intact subjects with early AD pathology. Our data suggest that increased expression of TrkB and Capzb2 accompanies adequate brain reserve in the initial stages of AD pathology. In subsequent stages of AD, the higher levels of TrkB and Capzb2 expression achieved may not be sufficient to prevent cognitive decline.
Alzheimer disease; Brain-derived neurotrophic factor (BDNF); Brain reserve; Capzb2; TrkB
Dysphagia is very common in patients with Parkinson’s disease (PD) and often leads to aspiration pneumonia, the most common cause of death in PD. Unfortunately, current therapies are largely ineffective for dysphagia. As pharyngeal sensation normally triggers the swallowing reflex, we examined pharyngeal sensory nerves in PD for Lewy pathology. Sensory nerves supplying the pharynx were excised from autopsied pharynges obtained from patients with clinically diagnosed and neuropathologically confirmed PD (n = 10) and healthy age-matched controls (n = 4). We examined: the glossopharyngeal nerve (IX); the pharyngeal sensory branch of the vagus nerve (PSB-X); and the internal superior laryngeal nerve (ISLN) innervating the laryngopharynx. Immunohistochemistry for phosphorylated α-synuclein was used to detect potential Lewy pathology. Axonal α-synuclein aggregates in the pharyngeal sensory nerves were identified in all of the PD subjects but not in the controls. The density of α-synuclein-positive lesions was significantly greater in PD subjects with documented dysphagia compared to those without dysphagia. In addition, α-synuclein-immunoreactive nerve fibers in the ISLN were much more abundant than those in the IX and PSBX. These findings suggest that pharyngeal sensory nerves are directly affected by the pathologic process of PD. This anatomic pathology may decrease pharyngeal sensation impairing swallowing and airway protective reflexes, thereby contributing to dysphagia and aspiration.
Alpha-synuclein aggregates; Dysphagia; Glossopharyngeal nerve; Immunohistochemistry; Internal superior laryngeal nerve; Lewy neurites; Nerve degeneration; Parkinson disease; Peripheral nervous system; Pharyngeal sensory nerves; Pharynx; Swallowing; Vagus nerve
A number of mechanisms have been proposed to contribute to the selective neuronal cell loss observed during Alzheimer disease (AD). These include the formation and accumulation of amyloid-β (Aβ)-containing plaques, neurofibrillary tangles (NFTs), and inflammatory processes mediated by astrocytes and microglia. Neuronal responses to such insults in AD brain include increased protein levels and immunoreactivity for kinases known to regulate cell cycle progression. One downstream target of these cell cycle regulatory proteins, the Retinoblastoma susceptibility gene product (pRb), has been shown to exhibit altered expression patterns in AD. Furthermore, in vitro studies have implicated pRb and one of the transcription factors it regulates, E2F1, in Aβ-induced cell death. To further explore the role of these proteins in AD, we examined the distribution of the E2F1 transcription factor and the hyperphosphorylated form of pRb (ppRb), which is unable to bind and regulate E2F activity, in the cortex of patients with AD and in non-demented controls. We observed increased ppRb and E2F1 immunoreactivity in AD brain, with ppRb predominately located in the nucleus and E2F1 in the cytoplasm. Although neither of these proteins significantly co-localized with NFTs, both ppRb and E2F1 were found in cells surrounding a subset of Aβ-containing plaques. These results support a role for G1 to S phase cell cycle regulators in AD.
Alzheimer disease; Amyloid plaque; Cell cycle; E2F1; Retinoblastoma protein; Transcription factor
Dysphagia (impaired swallowing) is common in Parkinson disease (PD) patients and is related to aspiration pneumonia, the primary cause of death in PD. Therapies that ameliorate the limb motor symptoms of PD are ineffective for dysphagia. This suggests that the pathophysiology of PD dysphagia may differ from that affecting limb muscles but little is known about potential neuromuscular abnormalities in the swallowing muscles in PD. This study examined the fiber histochemistry of pharyngeal constrictor (PC) and cricopharyngeal (CP) sphincter muscles in postmortem specimens from 8 PD and 4 age-matched control patients. Pharyngeal muscles in PD patients exhibited many atrophic fibers, fiber type grouping, and fast-to-slow myosin heavy chain transformation. These alterations indicate that the pharyngeal muscles experienced neural degeneration and regeneration over the course of PD. Notably, the PD patients with dysphagia had a higher percentage of atrophic myofibers vs. with those without dysphagia and controls. The fast-to-slow fiber type transition is consistent with abnormalities in swallowing, slow movement of food and increased tone in the CP sphincter in PD patients. The alterations in the pharyngeal muscles may play a pathogenic role in the development of dysphagia in PD patients.
Dysphagia; Fiber types; Immunohistochemistry; Muscle fiber atrophy; Myosin heavy chain isoforms; Parkinson disease; Pharyngeal constrictor muscles; Swallowing; Upper esophageal sphincter
The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. HARDI tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, hypothalamus, and basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may impact the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.
Arousal; Ascending reticular activating system (ARAS); Brainstem; Consciousness; High angular resolution diffusion imaging (HARDI); Neuroanatomy; Tractography
Pathologic TAR-DNA-binding protein 43 (TDP-43) is a disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis. We studied the presence, frequency, and distribution of TDP-43 pathology by immunohistochemistry and biochemistry in a series of clinically well-characterized tauopathy patient brains, including 182 Alzheimer disease (AD), 39 corticobasal degeneration, 77 progressive supranuclear palsy, and 12 Pick disease cases and investigated the clinical impact of concomitant TDP-43 pathology in these cases. TAR-DNA-binding protein 43 pathology was found in 25.8% of AD cases. It was restricted to the dentate gyrus and entorhinal cortex in approximately 75% of cases; approximately 25% showed more widespread TDP-43 pathology in frontal and temporal cortices, resembling the FTLD-U subtype associated with progranulin mutations. TAR-DNA-binding protein 43 pathology in AD was associated with significantly longer disease duration, but there was no association with the clinical presentation (148 cases diagnosed as AD and 34 cases diagnosed as frontotemporal lobar degeneration). Progressive supranuclear palsy and Pick disease cases showed no TDP-43 inclusions and no biochemical alterations of TDP-43. There was, however, a unique, predominantly glial TDP-43 pathology with staining of astrocytic plaque-like structures and coiled bodies in 15.4% of corticobasal degeneration cases; this was associated with biochemical TDP-43 changes similar to those in FTLD-U. These findings provide further insight into the burden and clinical significance of TDP-43 pathology in disorders other than FTLD-U and amyotrophic lateral sclerosis.
Alzheimer disease; Corticobasal degeneration; Frontotemporal dementia; Tauopathy; TDP-43
Niemann-Pick disease type C (NPC disease) is an incurable cellular lipid trafficking disorder characterized by neurodegeneration and intralysosomal accumulation of cholesterol and glycosphingolipids. Treatment with miglustat, a small imino sugar that reversibly inhibits glucosylceramide synthase, which is necessary for glycosphingolipid synthesis, has been shown to benefit patients with NPC disease. The mechanism(s) and extent of brain cellular changes underlying this benefit are not understood. To investigate the basis of the efficacy of miglustat, cats with disease homologous to the juvenile-onset form of human NPC disease received daily miglustat orally beginning at 3 weeks of age. The plasma half-life of miglustat was 6.6 ± 1.1 hours, with a tmax, Cmax, and area under the plasma concentration-time curve of 1.7 ± 0.6 hours, 20.3 ± 4.6 μg/ml, and 104.1 ± 16.6 μg hours/ml, respectively. Miglustat delayed the onset of neurological signs and increased the lifespan of treated cats, and was associated with decreased GM2 ganglioside accumulation in the cerebellum and improved Purkinje cell survival. Ex vivo examination of microglia from the brains of treated cats revealed normalization of CD1c and class II major histocompatibility complex expression, as well as generation of reactive oxygen species. Together, these results suggest that prolonged Purkinje cell survival, reduced glycosphingolipid accumulation, and/or the modulation of microglial immunophenotype and function contribute to miglustat-induced neurological improvement in treated cats.
Animal model; Cholesterol; Feline model; Glucosylceramide synthase; Glycosphingolipid; Miglustat; Niemann Pick
The purpose of this study was to identify differences in patterns of developmental abnormalities between the brains of individuals with autism of unknown etiology and those of individuals with duplications of chromosome 15q11.2-q13 [dup(15)] and autism, and to identify alterations that may contribute to seizures and sudden death in the latter. Brains of 9 subjects with dup(15), 10 with idiopathic autism, and 7 controls were examined. In the dup(15) cohort, 7 subjects (78%) had autism, 7 (78%) had seizures, and 6 (67%) had experienced sudden unexplained death. Subjects with dup(15) autism were microcephalic, with mean brain weights 300 g less (1,177 g) than those of subjects with idiopathic autism (1,477 g; p < 0.001). Heterotopias in the alveus, CA4, and dentate gyrus and dysplasia in the dentate gyrus were detected in 89% of dup(15) autism cases but in only 10% idiopathic autism cases (p < 0.001). By contrast, cerebral cortex dysplasia was detected in 50% of subjects with idiopathic autism and in no dup(15) autism cases (p < 0.04). The different spectrum and higher prevalence of developmental neuropathological findings in the dup(15) cohort than in cases with idiopathic autism may contribute to the high risk of early onset of seizures and sudden death.
Autism; Chromosome 15q11.2-q13 duplication; Developmental brain alterations; Seizures; Sudden unexpected death
The abundant axonal microtubule-associated protein tau regulates microtubule and actin dynamics, thereby contributing to normal neuronal function. We examined whether mice deficient in tau (Tau−/−) or with high levels of human tau differ from wild-type (WT) mice in their susceptibility to neuroaxonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. After sensitization with MOG35–55, there was no difference in clinical disease course between human tau and WT mice, but Tau−/− mice had more severe clinical disease and significantly more axonal damage in spinal cord white matter than those in WT mice. Axonal damage in gray matter correlated with clinical severity in individual mice. By immunoblot analysis, the early microtubule-associated protein-1b was increased 2-fold in the spinal cords of Tau−/− mice with chronic experimental autoimmune encephalomyelitis versus naive Tau−/− mice. This difference was not detected in comparable WT animals, which suggests that there was compensation for the loss of tau in the deficient mice. In addition, levels of the growth arrest–specific protein 7b, a tau-binding protein that is stabilized when bound to tau, were higher in WT than those in Tau−/− spinal cord samples. These data indicate that loss of tau exacerbates experimental autoimmune encephalomyelitis and suggest that maintaining tau integrity might reduce the axonal damage that occurs in inflammatory neurodegenerative diseases such as multiple sclerosis.
Axonal damage; Experimental autoimmune encephalomyelitis; Growth arrest–specific protein 7b; Microtubule-associated protein 1b; Multiple sclerosis; Myelin oligodendrocyte glycoprotein (MOG); Tau
Traumatic brain injury (TBI) causes cell death predominantly in the cerebral cortex but there is additional secondary cell death in the hippocampus. We previously found that the majority of the dying cells in the mouse hippocampus are newborn immature granular neurons in a mouse model of lateral controlled cortical impact (CCI) injury with a moderate level of impact. It is not known how long this selective cell death in the hippocampal dentate gyrus lasts, and how it is induced. Using Fluoro-Jade B and immunohistochemistry, we show that most of the neuron death in the hippocampus occurs within 24 hours post-TBI and that cell death continues at low level for at least another 2 wks in this lateral CCI model. The majority of the dying immature granular neurons did not exhibit morphological characteristics of apoptosis and only a small subpopulation of the dying cells was positive for apoptotic markers. In contrast, most of the dying cells co-expressed the receptor-interacting protein-1, a marker of necrosis, suggesting that immature neurons mainly died of necrosis. These results indicate that moderate TBI mainly triggers rapid necrotic death of immature neurons in the hippocampus in a mouse CCI model.
Apoptosis; Cell Death; Hippocampus; Mouse model; Necrosis; Traumatic Brain Injury
The neuropathological examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently employed clinical diagnostic methods, clinical and neuropathological data from the National Alzheimer's Coordinating Center (NACC), which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer's Disease Centers (ADCs), were collected as part of the NACC Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on “probable” and “possible” AD levels of clinical confidence and 4 levels of neuropathological confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathological criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathological diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in demented subjects than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiological studies.
Alzheimer disease; Autopsy; Clinical trials; Diagnosis; Histopathology; Neuropathology; Non-Alzheimer dementia
Defects in synaptic development and plasticity may lead to autism. Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptogenesis and synaptic plasticity. BDNF is synthesized as a precursor, pro-BDNF, which can be processed into either a truncated form or into mature BDNF. Previous studies reported increased BDNF-immunoreactive protein in autism, but the mechanism of this increase has not been investigated. We examined BDNF mRNA by real-time reverse transcription–polymerase chain reaction and BDNF protein by Western blotting and enzyme-linked immunosorbent assay in postmortem fusiform gyrus tissue from 11 patients with autism and 14 controls. BDNF mRNA levels were not different in the autism versus control samples, but total BDNF-like immunoreactive protein, measured by enzyme-linked immunosorbent assay, was greater in autism than in controls. Western blotting revealed greater pro-BDNF and less truncated BDNF in autism compared with controls. These data demonstrate that increased levels of BDNF-immunoreactive protein in autism are not transcriptionally driven. Increased pro-BDNF and reduced truncated BDNF are consistent with defective processing of pro-BDNF to its truncated form. Distortion of the balance among the 3 BDNF isoforms, each of which may exhibit different biological activities, could lead to changes in connectivity and synaptic plasticity and, hence, behavior. Thus, imbalance in proteolytic isoforms is a possible new mechanism for altered synaptic plasticity leading to autism.
PMID: 22437340 CAMSID: cams2282
Autism; Fusiform gyrus; mRNA; pro-BDNF; Protein isoforms; Proteolytic processing; truncated BDNF
Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approach to identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinical dementia rating score and postmortem brain pathological diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD.
Aging; 8-hydroxyguanosine; Mild cognitive impairment; Neurodegeneration; Oxidative damage; Preclinical Alzheimer disease; RNA
Axonal injury is consistently observed following traumatic brain injury (TBI). Prior research has extensively characterized the post-TBI response in myelinated axons. Despite evidence that unmyelinated axons comprise a numerical majority of cerebral axons, pathological changes in unmyelinated axons following TBI have not been systematically studied. To identify morphological correlates of functional impairment of unmyelinated fibers following TBI, we assessed ultrastructural changes in corpus callosum axons. Adult rats received moderate fluid percussion TBI, which produced diffuse injury with no contusion. Cross-sectional areas of 13,797 unmyelinated, and 3,278 intact myelinated axons were stereologically measured at survival intervals from 3 hours to 15 days post-injury. The mean caliber of unmyelinated axons was significantly reduced at 3 to 7 days, and recovered by 15 days, but the time course of this shrinkage varied among the genu, mid-callosum and splenium. Relatively large unmyelinated axons appeared to be particularly vulnerable. Injury-induced decreases in unmyelinated fiber density were also observed but they were more variable than caliber reductions. By contrast, no significant morphometric changes were observed in myelinated axons. The finding of a preferential vulnerability in unmyelinated axons has implications for current concepts of axonal responses following TBI and for development of specifically targeted therapies.
Axonal injury; Corpus callosum; Stereology; Traumatic brain injury; Ultrastructure; Unmyelinated axons