RESUMEN
Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Enfermedad de Niemann-Pick Tipo C/metabolismo , Acetilcisteína/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patología , Células Cultivadas , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones Endogámicos BALB C , Ratones Transgénicos , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/tratamiento farmacológico , Enfermedad de Niemann-Pick Tipo C/genética , Enfermedad de Niemann-Pick Tipo C/patología , Proteínas/genética , Proteínas/metabolismo , Médula Espinal/metabolismo , Médula Espinal/patología , beta-Ciclodextrinas/farmacologíaRESUMEN
BACKGROUND: Pathologic changes in the Alzheimer disease (AD) brain occur in a hierarchical neuroanatomical pattern affecting cortical, subcortical, and limbic regions. OBJECTIVE: To define the time course of pathologic and biochemical changes-amyloid deposition, amyloid beta-peptide (Abeta) accumulation, neurofibrillary tangle (NFT) formation, synaptic loss, and gliosis-within the temporal association cortex of AD cases of varying disease duration, relative to control brains. METHODS: Stereologic assessments of amyloid burden and tangle density as well as ELISA-based measurements of Abeta, synaptophysin, and glial fibrillary acidic protein (GFAP) were performed in the superior temporal sulcus from a cohort of 83 AD and 26 nondemented control brains. RESULTS: Relative to control cases, AD brains were characterized by accumulation of NFT and amyloid plaques, increase of tris- and formic acid-extractable Abeta species, reduced levels of synaptophysin, and elevated levels of GFAP. In AD cases, the duration of dementia correlated with the degree of tangle formation, gliosis, and synaptic loss but not with any Abeta measures. Accumulation of Abeta, measured both neuropathologically and biochemically, was markedly increased in AD brains independent of disease duration, even in cases of short duration. CONCLUSIONS: These data support distinct processes in the initiation and progression of AD pathology within the temporal cortex: Deposition of Abeta reaches a "ceiling" early in the disease process, whereas NFT formation, synaptic loss, and gliosis continue throughout the course of the illness.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Encéfalo/patología , Gliosis/patología , Ovillos Neurofibrilares/patología , Sinapsis/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4 , Apolipoproteínas E/genética , Biomarcadores/análisis , Encéfalo/metabolismo , Progresión de la Enfermedad , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/metabolismo , Humanos , Fragmentos de Péptidos/metabolismo , Valor Predictivo de las Pruebas , Sinaptofisina/metabolismoRESUMEN
BACKGROUND: Effective in vivo T-cell depletion is a critical component of many transplantation tolerance protocols. We have previously demonstrated T-cell depletion in miniature swine using a CRM9-based CD3-immunotoxin, pCD3-CRM9. CRM9 is a mutant form of diphtheria toxin (DT) that binds less efficiently than wild-type DT to the DT receptor (proHB-EGF) of primates. In this report, we describe and characterize the dose-dependent neurotoxicity associated with CRM9-based immunotoxin administration in swine. METHODS: Miniature swine were treated with varying doses of pCD3-CRM9 followed by daily monitoring for symptoms of neuropathy, including limb weakness, paresis, sluggishness, and/or respiratory distress. Animals demonstrating severe respiratory distress were euthanized and peripheral nerve, spinal cord, and skeletal muscle tissue samples were obtained at autopsy for microscopic examination. Unconjugated CRM9 was administered to one animal to define its toxicity independent of the effects of T-cell depletion. RESULTS: Excellent T-cell depletion was obtained using doses of pCD3-CRM9 greater than 0.1 mg/kg. However, neurotoxicity was observed at these doses, as manifested by transient muscle weakness or paresis, which in some cases progressed to respiratory failure and death. Dorsal root ganglia samples revealed pathological changes typical of diphtheritic polyneuropathy. The animal receiving unconjugated CRM9 exhibited the same neurotoxic side effects as those receiving the pCD3-CRM9 conjugate. CONCLUSIONS: Administration of pCD3-CRM9 immunotoxin provides excellent T-cell depletion in miniature swine but is associated with significant dose-dependent neurotoxicity. A possible reason for CRM9-associated neurotoxicity in swine, but not primates, is suggested on the basis of a known amino acid difference in the exodomain of the DT receptor (proHB-EGF) of swine compared with that of primates.
Asunto(s)
Toxina Diftérica/toxicidad , Inmunotoxinas/toxicidad , Polineuropatías/inducido químicamente , Secuencia de Aminoácidos , Animales , Proteínas Bacterianas/administración & dosificación , Proteínas Bacterianas/genética , Proteínas Bacterianas/toxicidad , Toxina Diftérica/administración & dosificación , Toxina Diftérica/genética , Factor de Crecimiento Similar a EGF de Unión a Heparina , Humanos , Inmunotoxinas/administración & dosificación , Inmunotoxinas/genética , Péptidos y Proteínas de Señalización Intercelular , Depleción Linfocítica/efectos adversos , Datos de Secuencia Molecular , Mutación , Polineuropatías/inmunología , Polineuropatías/patología , Receptores de Superficie Celular/genética , Homología de Secuencia de Aminoácido , Porcinos , Porcinos Enanos , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunologíaRESUMEN
Insights into mechanisms of familial Alzheimer's disease (AD) caused by genetic mutations have emerged rapidly compared to sporadic AD. Indeed, despite identification of several sporadic AD risk factors, it remains enigmatic how or why they predispose to neurodegenerative disease. For example, traumatic brain injury (TBI) predisposes to AD, and recurrent TBI in career boxers may cause a progressive memory disorder associated with AD-like brain pathology known as dementia pugilistica (DP). Although the reasons for this are unknown, repeated TBI may cause DP by mechanisms similar to those involved in AD. To investigate this possibility, we compared the molecular profile of tau pathologies in DP with those in AD and showed that the same tau epitopes map to filamentous tau inclusions in AD and DP brains, while the abnormal tau proteins isolated from DP brains are indistinguishable from the six abnormally phosphorylated brain tau isoforms in AD brains. Thus, these data suggest that recurrent TBI may cause DP by activating pathological mechanisms similar to those that cause brain degeneration due to accumulations of filamentous tau lesions in AD, and similar, albeit attenuated, activation of these processes by a single TBI may increase susceptibility to sporadic AD decades after the event.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Traumatismos en Atletas/metabolismo , Boxeo/lesiones , Lesiones Encefálicas/metabolismo , Sistema Nervioso Central/metabolismo , Neuronas/metabolismo , Proteínas tau/metabolismo , Anciano , Enfermedad de Alzheimer/patología , Traumatismos en Atletas/patología , Traumatismos en Atletas/fisiopatología , Western Blotting , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Sistema Nervioso Central/lesiones , Sistema Nervioso Central/patología , Epítopos/inmunología , Humanos , Inmunohistoquímica , Masculino , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Neuronas/patología , Fosforilación , Isoformas de Proteínas/metabolismoRESUMEN
The primary neuroaxonal dystrophies (NAD), which include infantile NAD and Hallervorden-Spatz syndrome (HSS), are characterized by dystrophic terminal axons and axonal swellings. Lewy bodies have been found in some cases. In Parkinson disease (PD) and dementia with Lewy bodies (DLB), Lewy bodies and neurites display prominent alpha-synuclein immunoreactivity. We examined 2 cases of HSS and 4 cases of infantile NAD with alpha-synuclein immunohistochemistry to test the hypothesis that these disorders with similar morphological findings might share a biochemical phenotype. Furthermore, we compared them to 8 cases of secondary or physiologic NAD of various causes and 2 cases of recent traumatic head injury. Alpha-synuclein positive neuronal cytoplasmic inclusions, including Lewy bodies, and neurites were numerous in 1 HSS and 1 infantile NAD case. In addition, axonal spheroids were immunostained in all 6 cases of primary NAD, 5 cases of secondary NAD, and 2 cases of recent head injury. Axonal spheroids were faintly stained in the 3 physiologic NAD cases. Alpha-synuclein positive axonal swellings may suggest a mechanism, such as axonal injury, leading to the neuronal cytoplasmic accumulation of alpha-synuclein in NAD and other disorders.
Asunto(s)
Axones/metabolismo , Axones/patología , Lesiones Encefálicas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Distrofias Neuroaxonales/metabolismo , Neurodegeneración Asociada a Pantotenato Quinasa/metabolismo , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Citoplasma/metabolismo , Femenino , Humanos , Inmunohistoquímica , Cuerpos de Inclusión/metabolismo , Masculino , Persona de Mediana Edad , Neuritas/metabolismo , Neurópilo/metabolismo , Sinucleínas , Ubiquitinas/metabolismo , alfa-SinucleínaRESUMEN
The Khachaturian criteria and the Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria for the neuropathological assessment of Alzheimer disease (AD) emphasize senile or neuritic plaques, age, and clinical history. A new scheme stressing topographic staging of neurofibrillary changes in addition to neuritic plaques has been proposed by the National Institute on Aging (NIA)-Reagan Institute Consensus Conference. This scheme assigns cases to high, intermediate, or low likelihood categories that the dementia is due to AD. We applied this method to 84 brains from subjects with clinical and neuropathological diagnoses of AD (n = 33), non-AD dementing illnesses (n = 34), including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP), and no neurological disease (n = 17). We also used Khachaturian and CERAD criteria. Neurofibrillary tangle and neuropil thread densities were assessed on 6-micrometer-thick modified Bielschowsky-stained paraffin sections from entorhinal-perirhinal cortex, CA1 of hippocampus, and neocortex including inferior temporal, visual association, and primary visual cortices. Each case was assigned a Braak and Braak stage. Using the NIA-Reagan criteria, we found excellent agreement between clinical history of AD dementia and brains assigned to the high likelihood category that dementia was due to AD. Among brains diagnosed neuropathologically with other degenerative diseases, NIA-Reagan criteria were more conservative than previous criteria, and these cases were likely to be categorized as intermediate or low likelihood that dementia was due to AD. All brains from nondemented subjects were assigned to the low (81%) or intermediate (19%) categories. In summary, we found good correlation between the NIA-Reagan criteria and clinical dementia, and there was generally good agreement between these criteria and existing neuropathological methods, Khachaturian and CERAD, in diagnosing AD. In studying several other neurodegenerative diseases, such as DLB, which shows neuropathological and clinical overlap with AD, the staging of neurofibrillary changes offered potential diagnostic refinement.
Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Sistema de Registros , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/patología , Diagnóstico Diferencial , Corteza Entorrinal/patología , Femenino , Hipocampo/patología , Humanos , Cuerpos de Lewy/patología , Masculino , Ovillos Neurofibrilares/patología , Neurópilo/patología , Placa Amiloide/patología , Estándares de Referencia , Parálisis Supranuclear Progresiva/patología , Lóbulo Temporal/patología , Corteza Visual/patologíaRESUMEN
Central pontine myelinolysis (CPM) was first described in 1959 and only later was associated with a rapid, sustained rise in serum sodium from a hyponatremic baseline. This discovery in 1981 led to modifications in recommendations for clinical treatment of hyponatremia. Our interest has been in tracking the incidence of CPM found at autopsy by year to see whether changes in medical treatment in hyponatremia have resulted in a decrease in CPM over time. Clinically asymptomatic CPM found at autopsy has always been at least as frequent as cases diagnosed premortem and serves as a reasonable indicator for the incidence of the disease. In over 3,000 autopsies, on most of which the brain was examined macroscopically and microscopically by the same neuropathologist, we have discovered 15 cases of asymptomatic, small pontine CPM. Of these 15, 6 were active lesions and 9 were remote; in the active group, 5 of the 6 cases were associated with a rapid, sustained rise in serum sodium during the appropriate time period. The incidence of asymptomatic CPM has remained steady over the 13-year time period. In contrast, we have encountered no cases of CPM diagnosed premortem that have come to autopsy in the same time period. These cases emphasize that CPM still occurs, but most often as an asymptomatic disorder with small, midline pontine lesions. When small active CPM is found, it still is associated with a rapid sustained rise in serum sodium.