RESUMEN
Reduced expression of brain-derived neurotrophic factor (BDNF) has a crucial role in the pathogenesis of Alzheimer's disease (AD), which is characterized with the formation of neuritic plaques consisting of amyloid-beta (Aß) and neurofibrillary tangles composed of hyperphosphorylated tau protein. A growing body of evidence indicates a potential protective effect of BDNF against Aß-induced neurotoxicity in AD mouse models. However, the direct therapeutic effect of BDNF supplement on tauopathy in AD remains to be established. Here, we found that the BDNF level was reduced in the serum and brain of AD patients and P301L transgenic mice (a mouse model of tauopathy). Intralateral ventricle injection of adeno-associated virus carrying the gene encoding human BDNF (AAV-BDNF) achieved stable expression of BDNF gene and restored the BDNF level in the brains of P301L mice. Restoration of the BDNF level attenuated behavioral deficits, prevented neuron loss, alleviated synaptic degeneration and reduced neuronal abnormality, but did not affect tau hyperphosphorylation level in the brains of P301L mice. Long-term expression of AAV-BDNF in the brain was well tolerated by the mice. These findings suggest that the gene delivery of BDNF is a promising treatment for tau-related neurodegeneration for AD and other neurodegenerative disorders with tauopathy.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/farmacología , Encéfalo/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Expresión Génica/genética , Tauopatías/tratamiento farmacológico , Tauopatías/genética , Enfermedad de Alzheimer/patología , Animales , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Inyecciones Intraventriculares , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genéticaRESUMEN
Alzheimer's disease (AD) is the primary cause of dementia in the elderly. The ectodomain of p75 neurotrophin receptor (p75NTR-ECD) has been suggested to play important roles in regulating beta-amyloid (Aß) deposition and in protecting neurons from the toxicity of soluble Aß. However, whether and how the serum and cerebrospinal fluid (CSF) levels of p75NTR-ECD change in patients with AD are not well documented. In the present study, we determined the concentrations of serum p75NTR-ECD in an AD group, a Parkinson disease group and a stroke group, as well as in a group of elderly controls without neurological disorders (EC). We also determined the levels of CSF p75NTR-ECD in a subset of the AD and EC groups. Our data showed that a distinct p75NTR-ECD profile characterized by a decreased CSF level and an increased serum level was present concomitantly with AD patients but not with other diseases. p75NTR-ECD levels in both the serum and CSF were strongly correlated with Mini-Mental State Examination (MMSE) scores and showed sound differential diagnostic value for AD. Moreover, when combining CSF Aß42, CSF Aß42/40, CSF ptau181 or CSF ptau181/Aß42 with CSF p75NTR-ECD, the area under the receiver operating characteristic curve (AUC) and diagnostic accuracies improved. These findings indicate that p75NTR-ECD can serve as a specific biomarker for AD and the determination of serum and CSF p75NTR-ECD levels is likely to be helpful in monitoring AD progression.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Proteínas del Tejido Nervioso , Fragmentos de Péptidos/metabolismo , Receptores de Factor de Crecimiento Nervioso , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Antígenos CD/sangre , Antígenos CD/líquido cefalorraquídeo , Área Bajo la Curva , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Diagnóstico Diferencial , Precisión de la Medición Dimensional , Progresión de la Enfermedad , Femenino , Humanos , Pruebas de Inteligencia , Persona de Mediana Edad , Proteínas del Tejido Nervioso/sangre , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Neuroprotección/fisiología , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/diagnóstico , Valor Predictivo de las Pruebas , Receptores de Factor de Crecimiento Nervioso/sangre , Estadística como Asunto , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/líquido cefalorraquídeo , Accidente Cerebrovascular/diagnósticoRESUMEN
In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aß) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aß and mediates Aß-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aß. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aß deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aß deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing ß-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aß toxicity and would be a novel therapeutic target and biomarker for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Encéfalo/patología , Proteínas del Tejido Nervioso/química , Estructura Terciaria de Proteína/fisiología , Receptores de Factor de Crecimiento Nervioso/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Factores de Edad , Enfermedad de Alzheimer/complicaciones , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/toxicidad , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Estudios de Casos y Controles , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/terapia , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Humanos , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Mutación/genética , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Presenilina-1/genética , Receptores de Factor de Crecimiento Nervioso/deficiencia , Receptores de Factor de Crecimiento Nervioso/genética , Proteínas Recombinantes/uso terapéutico , Transducción GenéticaRESUMEN
BACKGROUND AND PURPOSE: Previous studies suggested that the overall burden of prior infections contributes to cardiovascular diseases and stroke. In the present study, the association between infectious burden (IB) and Alzheimer's disease (AD) was examined. METHODS: Antibody titers to common infectious pathogens including cytomegalovirus (CMV), herpes simplex virus type 1 (HSV-1), Borrelia burgdorferi, Chlamydophila pneumoniae and Helicobacter pylori were measured by enzyme-linked immunosorbent assay in 128 AD patients and 135 healthy controls. IB was defined as a composite serological measure of exposure to these common pathogens. RESULTS: Seropositivities toward zero-two, three and four-five of these pathogens were found in 44%, 40% and 16% of healthy controls but in 20%, 44% and 36% of AD patients, respectively. IB, bacterial burden and viral burden were independently associated with AD after adjusting for age, gender, education, APOE genotype and various comorbidities. Mini-Mental State Examination scores were negatively correlated with IB in all cases. Serum beta-amyloid protein (Aß) levels (i.e. Aß40, Aß42 and total Aß) and inflammatory cytokines (i.e. interferon-γ, tumor necrosis factor α, interleukin-1ß and interleukin-6) in individuals exposed to four-five infectious pathogens were significantly higher than those exposed to zero-two or three pathogens. CONCLUSIONS: IB consisting of CMV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with AD. This study supports the role of infection/inflammation in the etiopathogenesis of AD.
Asunto(s)
Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Infecciones Bacterianas/sangre , Infecciones por Herpesviridae/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
We found previously that genes injected into skeletal muscle can be taken up by myofibers and expressed. In the present study we found that myocardial cells can also express a variety of reporter genes injected into myocardium as efficiently as skeletal myofibers, while the cells of several other tissues cannot. The inability of tissues other than striated muscle to express injected DNA is not due to technical difficulties of injection because injected DNA was detected in these other tissues by PCR analysis. These results suggest that skeletal and cardiac muscle cells have unique features such as T tubules that may play a critical role in DNA uptake. Expression in cardiac muscle was stable for only two weeks, possibly because of an immune response against the transfected cells. The ability to directly transfer genes into myocardial cells raises the possibility of gene therapy for both acquired and genetic heart diseases.
Asunto(s)
Miocardio , Proteínas Recombinantes de Fusión/biosíntesis , Transfección , Animales , Secuencia de Bases , Ciclosporinas/farmacología , ADN/administración & dosificación , ADN/genética , Espacio Extracelular , Regulación de la Expresión Génica , Síndromes de Inmunodeficiencia/inducido químicamente , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/metabolismo , Luciferasas/biosíntesis , Luciferasas/genética , Ratones , Microinyecciones , Datos de Secuencia Molecular , Músculos/metabolismo , Miocardio/metabolismo , Especificidad de Órganos , Plásmidos , Reacción en Cadena de la Polimerasa , Ratas , Ratas Desnudas , Proteínas Recombinantes de Fusión/genética , beta-Galactosidasa/biosíntesis , beta-Galactosidasa/genéticaRESUMEN
A novel population of spinal neurons is shown to terminate in two nuclei: the lateral cervical nucleus and the dorsal column nuclei. Nuclear yellow and Fast blue injected respectively into these nuclei are retrogradely transported to common neurons in the lumbosacral dorsal horn. The bifurcation of these neurons' axons appears to occur at the cervico-thoracic junction. These results indicate that some dorsal horn neurons transmit sensory information to two distinct nuclei. The two projections and their branching points may play a special role in neuronal communication.
Asunto(s)
Neuronas/citología , Médula Espinal/anatomía & histología , Nervios Espinales/citología , Animales , GatosRESUMEN
Questions arising from recent clinical neural transplantation trials in Parkinson's disease have under-scored the necessity for a thorough experimental evaluation of the structural and functional consequences of this procedure. The present study investigated the neuroanatomical host reaction to intrastriatal implants in normal and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated nonhuman primates. Nine monkeys (Cebus apella) received intrastriatal implants using either a stereotactic approach with a silver tissue carrier or an open microsurgical procedure. Seven of these animals received intrastriatal adrenal medullary autografts, while two received control implants consisting of the tissue carrier alone. One month following transplantation, the hosts' brains were evaluated via immunohistochemical and routine histologic methods. In both MPTP-treated and normal monkeys, enhanced ipsilateral expression of tyrosine hydroxylase-like immunoreactive (TH-IR) fibers in the caudate nucleus was observed, despite minimal survival of adrenal chromaffin cells in the implants. The intensity of this response was greatest adjacent to the implant site, but a clearly increased degree of ipsilateral striatal fiber staining also could be seen several millimeters from the graft. TH-IR fibers also were more dense and of thicker caliber throughout the nigrostriatal and mesolimbic pathways ipsilateral to the implant. Control stereotactic implants, consisting of a silver tissue carrier alone, produced a similar enhancement of immunoreactive fibers, suggesting an induction of TH-IR fibers by the parenchymal injury produced during surgical implantation. There are two major hypotheses proposed to explain why adrenal medullary grafts may promote functional recovery in human parkinsonism: (1) replacement of lost striatal neurotransmitter (dopamine) by the viable grafted tissue, or (2) induction of recovery of remaining host dopaminergic systems by the implantation procedure. Our current data appear to support the latter.
Asunto(s)
Médula Suprarrenal/trasplante , Ganglios Basales/fisiología , Regeneración Nerviosa , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Ganglios Basales/enzimología , Núcleo Caudado/enzimología , Cebus , Cuerpo Estriado/fisiología , Inmunohistoquímica , Microcirugia , Piridinas/farmacología , Técnicas Estereotáxicas , Distribución Tisular , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Based largely upon studies done in rats, a number of medical centers are now performing autografts of adrenal medullary tissue in consenting patients with Parkinson's disease. However, a systematic experimental evaluation of adrenal medullary autografts in nonhuman primates is necessary. This study provides a detailed analysis of the implant site at the fine structural level 30 days post-transplantation in the Cebus monkey. Five normal and two 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-treated Cebus monkeys received adrenal medullary autografts using an open microsurgical approach (n = 3) or via stereotactic placement with a tissue carrier (n = 4). Analysis of preimplant samples of the adrenal medulla confirmed that viable chromaffin cells were implanted into the basal ganglia. However, 30 days later, the implant site resembled a chronic inflammatory focus, with grafted chromaffin cells identified ultrastructurally in only two of the seven transplanted monkeys. The grafted cells showed overt signs of cellular degeneration and were surrounded by phagocytic macrophages. All of the implant sites, regardless of the surgical approach, were filled with macrophages, cells of hematogenous origin, and fibrous astrocytes. The vasculature of the implant site was of the nonfenestrated type, characteristic of the host striatum. Despite the poor survival of implanted chromaffin cells, robust sprouting of tyrosine hydroxylase-like immunoreactive fibers was evident in the striatum adjacent to the implant site (see accompanying manuscript, M.S. Fiandaca, J. H. Kordower, J.T. Hansen, S.-S. Jiao, and D.M. Gash, 1988, Exp. Neurol. 102: 76-91), suggesting that implantation may have precipitated a host response that was beneficial to the transplanted animal. Additional studies that provide a better understanding of the cellular elements residing in the implant site and their potential for trophic influence seem warranted.
Asunto(s)
Médula Suprarrenal/trasplante , Ganglios Basales/fisiología , Supervivencia de Injerto , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Médula Suprarrenal/citología , Médula Suprarrenal/ultraestructura , Animales , Ganglios Basales/citología , Ganglios Basales/ultraestructura , Cebus , Sistema Cromafín/citología , Sistema Cromafín/ultraestructura , Inmunohistoquímica , Microscopía Electrónica , Piridinas/farmacología , Trasplante AutólogoAsunto(s)
Médula Suprarrenal/trasplante , Núcleo Caudado/fisiopatología , Enfermedad de Parkinson/terapia , Adulto , Dopamina/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Norepinefrina/líquido cefalorraquídeo , Enfermedad de Parkinson/líquido cefalorraquídeo , Enfermedad de Parkinson/fisiopatologíaRESUMEN
The quantitative development of brain and brain components with respect to body-size is discussed comparatively for the Chinese Giant Panda, the Canadian Raccoon and the American Black Bear. The panda ranks highest in encephalization as well as in relative volumes of neocortex, cerebellum and six other parts. The raccoon exhibits the strongest development of olfactory elements. The bear stays below the other species, showing but a single index that is superior to the corresponding index in one of them only. These results must be considered within the context of recent debates on the systematic position of the panda. This animal appears to have followed a partly independent evolutionary pathway, although it seems to stand somewhat closer to the raccoon than to the bear, contrary to other views. New comparative eco-ethological studies of the three species, as a complement to our neuromorphological approach, would certainly clarify the status reached by the panda at the end of its long and lonely evolution.