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1.
Neuropathol Appl Neurobiol ; 38(4): 344-53, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21988073

RESUMO

AIMS: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. METHODS: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. RESULTS: We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. CONCLUSIONS: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.


Assuntos
Encéfalo/citologia , Demência Vascular , Células-Tronco Neurais/citologia , Neurogênese , Idoso de 80 Anos ou mais , Autopsia , Feminino , Humanos , Imuno-Histoquímica , Masculino
2.
Cell Prolif ; 44(2): 120-7, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21401753

RESUMO

OBJECTIVES: To characterize basal differentiation tendencies of a human embryonic stem (hES) cell line, KCL-002. MATERIALS AND METHODS: In vitro specification and differentiation of hES cells were carried out using embryoid body (EB) cultures and tests of pluripotency and in vivo differentiation were performed by teratoma assays in SCID mice. Real-time PCR, immunohistochemistry, flow cytometry and histological analyses were used to identify expression of genes and proteins associated with the ectodermal, endodermal and mesodermal germ layers. RESULTS: Undifferentiated KCL-002 cells expressed characteristic markers of pluripotent stem cells such as Nanog, Sox-2, Oct-4 and TRA 1-60. When differentiated in vitro as EB cultures, expression of pluripotency, endodermal and ectodermal markers decreased rapidly. In contrast, mesodermal and mesenchymal markers such as VEGFR-2, α-actin and vimentin increased during EB differentiation as shown by qPCR, immunostaining and flow cytometric analyses. Teratoma formation in SCID mice demonstrated the potential to form all germ layers in vivo with a greater proportion of the tumours containing mesenchymal derivatives. CONCLUSIONS: The data presented suggest that the KCL-002 hES cell line is pluripotent and harbours a bias in basal differentiation tendencies towards mesodermal and mesenchymal lineage cells. Characterizing innate differentiation propensities of hES cell lines is important for understanding heterogeneity between different cell lines and for further studies aimed at deriving specific lineages from hES cells.


Assuntos
Células-Tronco Embrionárias/citologia , Mesoderma/citologia , Actinas/genética , Actinas/metabolismo , Animais , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Diferenciação Celular , Linhagem Celular , Ectoderma/metabolismo , Células-Tronco Embrionárias/metabolismo , Endoderma/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Mesoderma/metabolismo , Camundongos , Proteína Homeobox Nanog , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Proteoglicanas/genética , Proteoglicanas/metabolismo , Fatores de Transcrição SOXB1/genética , Fatores de Transcrição SOXB1/metabolismo , Transplante Heterólogo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
3.
Gene Ther ; 18(1): 1-6, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20882052

RESUMO

The central nervous system has limited capacity of regenerating lost tissue in slowly progressive, degenerative neurological conditions such as Parkinson's disease (PD), Alzheimer's disease or Huntington's disease (HD), or in acute injuries resulting in rapid cell loss for example, in cerebrovascular damage (for example, stroke) or spinal cord injury. Although the adult brain contains small numbers of stem cells in restricted areas, they do not contribute significantly to functional recovery. Transplantation of stem cells or stem cell-derived progenitors has long been seen as a therapeutic solution to repair the damaged brain. With the advent of the induced pluripotent stem cells technique a new and potentially better source for transplantable cells may be available in future. This review aims to highlight current strategies to replace lost cellular populations in neurodegenerative diseases with the focus on HD and PD and traumatic brain injuries such as stroke, discussing many of the technical and biological issues associated with central nervous system cell transplantation.


Assuntos
Doenças do Sistema Nervoso/terapia , Transplante de Células-Tronco , Animais , Lesões Encefálicas/terapia , Humanos , Modelos Biológicos , Doenças do Sistema Nervoso/metabolismo , Recuperação de Função Fisiológica , Células-Tronco/citologia , Células-Tronco/metabolismo
4.
Cell Prolif ; 42(1): 63-74, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19143764

RESUMO

OBJECTIVE: The maintenance of pluripotency of human embryonic stem cells (hESCs) requires a high efficiency of self-renewal. During in vitro propagation, however, hESCs have a propensity to differentiate spontaneously. In this study, we assessed the nature of hESC responses to hypoxic conditions. MATERIALS AND METHODS: Human embryonic stem cells were grown in normoxic and hypoxic conditions, and the cells expressing Oct4 and stage-specific embryonic antigen-1 were identified by indirect immunofluorescence. The transcriptional expression of Nanog, Notch1, and Oct4 was determined by a real-time reverse transcription-polymerase chain reaction, and the inhibition of Notch-mediated signalling was achieved with a gamma-secretase inhibitor. RESULTS: In contrast to culture at 21% oxygen, where the colonies displayed a marked degree of differentiation, we found that during exposure to 5% oxygen, the hESC colonies displayed a homogenous and flat morphology that was consistent with the presence of Oct4-positive phenotype, indicating no spontaneous differentiation. When cultured at 5% oxygen for either 4 weeks or up to 18 months, high levels of Nanog and Notch1 transcriptional expression were detected, albeit the expression was significantly lower during longer exposure. The suppression of differentiation was rapidly reversed on transfer of the hypoxic cultures to normoxic conditions. Looking into the molecular mechanisms of the maintenance of self-renewal at low oxygen tensions, we found that inhibition of Notch signalling fully abrogated the hypoxic induction of undifferentiated phenotype. CONCLUSION: Our data, thus, indicate that hypoxic exposure has the capacity to sustain long-term self-renewal of hESCs and that this effect is mediated through activation of Notch.


Assuntos
Diferenciação Celular , Hipóxia Celular , Células-Tronco Embrionárias/citologia , Receptores Notch/metabolismo , Sequência de Bases , Biomarcadores/metabolismo , Divisão Celular , Primers do DNA , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Biossíntese de Proteínas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Gênica
5.
Br J Pharmacol ; 155(3): 316-25, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18724383

RESUMO

Human embryonic stem cells are pluripotent cells derived from the inner cell mass of preimplantation stage embryos. Their unique potential to give rise to all differentiated cell types has generated great interest in stem cell research and the potential that it may have in developmental biology, medicine and pharmacology. The main focus of stem cell research has been on cell therapy for pathological conditions with no current methods of treatment, such as neurodegenerative diseases, cardiac pathology, retinal dysfunction and lung and liver disease. The overall aim is to develop methods of application either of pure cell populations or of whole tissue parts to the diseased organ under investigation. In the field of pulmonary research, studies using human embryonic stem cells have succeeded in generating enriched cultures of type II pneumocytes in vitro. On account of their potential of indefinite proliferation in vitro, embryonic stem cells could be a source of an unlimited supply of cells available for transplantation and for use in gene therapy. Uncovering the ability to generate such cell types will expand our understanding of biological processes to such a degree that disease understanding and management could change dramatically.


Assuntos
Pulmão/fisiologia , Regeneração , Transplante de Células-Tronco/métodos , Técnicas de Cultura de Células , Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/metabolismo , Células-Tronco Embrionárias/transplante , Humanos , Pulmão/embriologia
6.
Exp Gerontol ; 43(11): 1005-8, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18644431

RESUMO

Stem cells have been used to investigate developmental processes and may be used as a therapeutic source of material for regenerative medicine and cancer. Here we propose the use of human embryonic stem cells, which represent a youthful phenotype, as models for experimentally investigating human ageing.


Assuntos
Envelhecimento/fisiologia , Células-Tronco Embrionárias/citologia , Técnicas de Cultura de Células , Humanos , Modelos Biológicos , Medicina Regenerativa , Pesquisa
7.
Indian J Med Res ; 125(1): 17-24, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17332653

RESUMO

Due to lack of suitable organ donors, future degenerative diseases and traumas could be treated with stem cell engraftment. To do this, large numbers of cells must be grown and maintained in culture. These cells must also be capable to differentiate into all the cells of the body. Embryonic stem cells fulfill many of the necessary criteria for clinical translation for use in therapeutic transplantation for a myriad of diseases. There are still many issues including immunological, cell cycling and differentiation that must be overcome for them to reach their potential use in the clinical arena.


Assuntos
Células-Tronco Embrionárias/fisiologia , Células-Tronco Embrionárias/transplante , Humanos
8.
Reprod Biomed Online ; 14 Spec No 1: 67-73, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-20483401

RESUMO

The inner cell mass of the preimplantation blastocyst, from which all the cells of the body develop, is a source of embryonic stem cells. These cells can be maintained in their undifferentiated state over long periods in culture and yet retain their pluripotency. The generation of human stem cells capable of differentiating into all the cell types of the human body opens the way for the use of these cells in therapeutic transplantation for a myriad of diseases. However, as discussed here, there are a number of logistical, biological, and clinical hurdles that must be overcome prior to the use of these cells in routine clinical practice.

9.
Reprod Biomed Online ; 13(5): 725-31, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17169188

RESUMO

The inner cell mass of the preimplantation blastocyst, from which all the cells of the body develop, is a source of embryonic stem cells. These cells can be maintained in their undifferentiated state over long periods in culture and yet retain their pluripotency. The generation of human stem cells capable of differentiating into all the cell types of the human body opens the way for the use of these cells in therapeutic transplantation for a myriad of diseases. However, as discussed here, there are a number of logistical, biological, and clinical hurdles that must be overcome prior to the use of these cells in routine clinical practice.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Embrionárias/transplante , Transplante de Células-Tronco/métodos , Pesquisas com Embriões/ética , Humanos , Técnicas de Cultura de Órgãos/métodos , Política , Transplante de Células-Tronco/ética
11.
J Neuropathol Exp Neurol ; 60(10): 929-36, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11589423

RESUMO

Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protein synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and severity of dementia in AD remain unclear. We studied the presynaptic proteins synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferase (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects with AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 41% in the AD groups. Synaptic protein immunoreactivity and ChAT activity were correlated with Mini-Mental State Examination scores obtained 1 yr prior to death. When AD cases were subgrouped into mild/moderate and severe illness at time of death, all differences in presynaptic proteins and ChAT activity were significant between controls and severe cases. However, no significant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.


Assuntos
Doença de Alzheimer/patologia , Córtex Pré-Frontal/patologia , Terminações Pré-Sinápticas/patologia , Sinapses/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Análise de Variância , Colina O-Acetiltransferase/metabolismo , Feminino , Humanos , Modelos Lineares , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Córtex Pré-Frontal/enzimologia , Terminações Pré-Sinápticas/enzimologia , Proteínas Qa-SNARE , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Sinapses/enzimologia , Sinaptofisina/metabolismo , Proteína 25 Associada a Sinaptossoma
12.
Neurology ; 55(10): 1460-7, 2000 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-11094098

RESUMO

BACKGROUND: Noncognitive behavioral changes such as depression, aggressive behavior, psychosis, and overactivity occur frequently in patients with dementia, in addition to cognitive impairment, and often determine the need for institutionalization. The biochemical basis of such changes is poorly understood. Clinical trial data indicate that cholinomimetics improve noncognitive behaviors. This study investigated the relationship between markers of the cholinergic and dopaminergic neurotransmitter systems and noncognitive behavioral symptoms assessed during the course of dementing illness. METHOD: Brains from 46 patients with dementia (36 with AD and 10 with mixed or other dementias using Consortium to Establish a Registry for AD criteria) were examined together with 32 normal controls. The patients with dementia had been evaluated every 4 months, often over several years, for cognitive performance (Mini-Mental State Examination) and behavior (Present Behavioral Examination). Concentrations of dopamine (DA) and major metabolites, choline acetyltransferase activity (ChAT), and density (Bmax) of DA D1 receptors in frontal and temporal cortex were studied by radioligand binding protocols. None of the patients was receiving cholinomimetic drugs. RESULTS: ChAT activity, but no other neurochemical markers, was reduced in AD compared with controls. Loss of ChAT activity correlated with cognitive impairment. Lowered ChAT activity also correlated with increasing overactivity in patients with dementia in both frontal and temporal cortex whereas ChAT:DA and ChAT:D1 ratios in temporal cortex correlated negatively with aggressive behavior. CONCLUSIONS: Disturbance of the cholinergic system may underlie both cognitive and some noncognitive behavioral changes in dementia, providing a basis for rational therapy.-1467


Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/psicologia , Colina O-Acetiltransferase/metabolismo , Transtornos Mentais/enzimologia , Transtornos Mentais/psicologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Feminino , Humanos , Masculino , Transtornos Mentais/patologia , Escalas de Graduação Psiquiátrica , Ensaio Radioligante , Receptores de Dopamina D1/metabolismo
13.
Brain Res ; 831(1-2): 11-24, 1999 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-10411979

RESUMO

Vesicular transport events appear to be facilitated by the VAMP/synaptobrevin family of membrane proteins in the vesicle (v-SNAREs) and a heterodimeric complex of syntaxin and SNAP-23/25 family members in the target membrane (t-SNAREs). In this manuscript we examine the tissue distribution and composition of the heterodimeric t-SNARE complexes in adult rodent brain. Analysis of protein extracts from brain regions shows that SNAP-25, syntaxin 1, and 4 are broadly distributed, while SNAP-23, syntaxin 3, and 7 show distinct patterns of expression. Further immunohistochemistry and fractionation studies show that while SNAP-25 is enriched in axons and nerve terminals, SNAP-23 is concentrated in cell bodies. Both SNAP-23 and SNAP-25 associate with the plasma membrane and can be metabolically labeled with [(3)H] palmitate in AtT-20 cells. Anti-SNAP-25 antibodies co-immunoprecipitate t-SNARE heterodimers from brain extracts that predominantly contain syntaxin 1 and 2. Contrary to results from in vitro binding assays, SNAP-23 was found predominantly associated with syntaxin 3. These observations suggest that t-SNARE, heterodimer composition is governed more by SNARE expression and localization than by simple protein-protein affinity.


Assuntos
Encéfalo/metabolismo , Proteínas de Membrana/análise , Proteínas do Tecido Nervoso/análise , Sistemas Neurossecretores/fisiologia , Acilação , Animais , Axônios/química , Linhagem Celular , Imuno-Histoquímica , Neurônios/química , Proteínas R-SNARE , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/química , Proteína 25 Associada a Sinaptossoma , Sinaptossomos/química
14.
Brain Res ; 810(1-2): 181-99, 1998 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-9813316

RESUMO

Excitatory amino acids may promote microtubular proteolysis observed in ischemic neuronal degeneration by calcium-mediated activation of calpain, a neutral protease. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. Spontaneously hypertensive rats were treated with 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo-(F)quinoxaline (NBQX), a competitive antagonist of the neuronal receptor for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), or cis-4-[phosphono-methyl]-2-piperidine carboxylic acid (CGS 19755), a competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor. After treatment, all animals were subjected to permanent occlusion of the middle cerebral artery for 6 or 24 h. Infarct volumes measured in animals pretreated with CGS 19755 after 24 h of ischemia were significantly smaller than those quantified in ischemic controls. Rats pretreated with NBQX showed partial amelioration of cytoskeletal injury with preserved immunolabeling of microtubule-associated protein 2 (MAP 2) at 6 and 24 h and reduced accumulation of calpain-cleaved spectrin byproducts only at 6 h. Prevention of cytoskeletal damage was more effective after pretreatment with CGS 19755, as shown by retention of MAP 2 immunolabeling and significant restriction of calpain activity at both 6 and 24 h. Preserved immunolabeling of tau protein was observed at 6 and 24 h only in animals pretreated with CGS 19755. Western analysis performed on ischemic cortex taken from controls or rats pretreated with either NBQX or CGS 19755 suggested that loss of tau protein immunoreactivity was caused by dephosphorylation, rather than proteolysis. These results demonstrate a crucial link between excitotoxic neurotransmission, microtubular proteolysis, and neuronal degeneration in focal cerebral ischemia.


Assuntos
Calpaína/antagonistas & inibidores , Citoesqueleto/enzimologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ataque Isquêmico Transitório/enzimologia , Receptores de Glutamato/efeitos dos fármacos , Animais , Western Blotting , Infarto Cerebral/fisiopatologia , Citoesqueleto/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Ácidos Pipecólicos/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Espectrina/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Proteínas tau/metabolismo
15.
J Cereb Blood Flow Metab ; 16(6): 1189-202, 1996 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8898691

RESUMO

Calpain, a neutral protease activated by calcium, may promote microtubular proteolysis in ischemic brain. We tested this hypothesis in an animal model of focal cerebral ischemia without reperfusion. The earliest sign of tissue injury was observed after no more than 15 min of ischemia, with coiling of apical dendrites immunolabeled to show microtubule-associated protein 2 (MAP2). After 6 h of ischemia, MAP2 immunoreactivity was markedly diminished in the infarct zone. Quantitative Western analysis demonstrated that MAP2 was almost unmeasurable after 24 h of ischemia. An increase in calpain activity, shown by an antibody recognizing calpain-cleaved spectrin fragments, paralleled the loss of MAP2 immunostaining. Double-labeled immunofluorescent studies showed that intraneuronal calpain activity preceded evidence of MAP2 proteolysis. Perikaryal immunolabeling of tau protein became increasingly prominent between 1 and 6 h in neurons located within the transition zone between ischemic and unaffected tissue. Western blot experiments confirmed that dephosphorylation of tau protein occurred during 24 h of ischemia, but was not associated with significant loss of tau antigen. We conclude that focal cerebral ischemia is associated with early microtubular proteolysis caused by calpain.


Assuntos
Isquemia Encefálica/patologia , Proteínas Associadas aos Microtúbulos/análise , Microtúbulos/patologia , Animais , Isquemia Encefálica/metabolismo , Imuno-Histoquímica , Masculino , Ratos , Ratos Endogâmicos SHR
16.
Exp Neurol ; 141(1): 12-24, 1996 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8797663

RESUMO

The intracerebral transplantation of freshly dissected fetal tissue containing cholinergic neurons of the developing basal forebrain has been reported to reverse lesion-induced or age-related cognitive deficits in animal models of cholinergic neuronal degeneration. Grafts of cultured fetal neurons, however, have generally shown poor cellular survival and limited therapeutic benefit. We tested the hypothesis that recent advances in the identification of growth factors that promote the survival and propagation of fetal precursor cells in vitro would improve the long-term survival of cultured neurons following intracerebral implantation. Dissociated cells from gestational Day 14 rodent basal forebrain were grown in chemically defined media supplemented with 20 ng/ml basic fibroblast growth factor. Two weeks postplating, numerous cells were present in the cultures and showed immunoreactive labeling for a variety of markers, including glutamic acid decarboxylase, neuron-specific enolase, neurofilament proteins, glial fibrillary acidic protein and, occasionally, choline acetyltransferase. To determine if cultured basal forebrain cells would survive intracerebral implantation, the cells were implanted homotypically into the nucleus basalis magnocellularis. To enhance the potential for graft survival in vivo, cells were also implanted into the nucleus basalis magnocellularis following an ibotenic acid lesion and into the denervated frontal cortex. Animals sacrificed between 2 weeks and 7 months following transplantation showed good and comparable graft survival in all sites. Immunocytochemical analysis revealed that representative populations of cells observed in vitro survived for prolonged periods in vivo, even in sites distal from their normal cellular targets. Thus, neuronal populations expanded in vitro can successfully survive and maintain cellular phenotypes post-transplantation. These results suggest a potential for isolating and growing specific neuronal populations in vitro for intracerebral transplantation.


Assuntos
Transplante de Tecido Fetal , Fator 2 de Crescimento de Fibroblastos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/transplante , Prosencéfalo/citologia , Animais , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Feminino , Neurônios/citologia , Prosencéfalo/embriologia , Ratos , Ratos Endogâmicos F344 , Transplante de Células-Tronco , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Fatores de Tempo
17.
Exp Neurol ; 117(2): 124-38, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1499691

RESUMO

In Alzheimer's disease, a characteristic neurochemical abnormality is the loss of cholinergic enzymes in the neocortex, reflecting the degeneration of basal forebrain neurons responsible for cholinergic innervation of the neocortex. It is hypothesized that basal forebrain neuronal degeneration results from a reduction in the level of trophic factors synthesized by neurons in the target regions of cholinergic projections. Data from a large number of animal lesioning studies tend to support this theory; however, most of these lesions also induce widespread, nonspecific injury responses in the CNS. To directly test the dependence of basal forebrain cholinergic neurons on target-derived neurotrophic support, pregnant Sprague-Dawley rats were injected with moderate doses of methylazoxymethanol acetate (MAM) on Gestational Days 14 and 15. Extensive morphometric analysis of offspring reveals that the prenatal administration of MAM during this period of neurogenesis results in the ablation of 40-70% of cortical neurons, without significant effects on the hippocampus or the genesis of basal forebrain cholinergic neurons. Examination of MAM-treated animals at several ages reveals no significant differences in neuronal density of cholinergic neurons as compared to controls. Extensive analysis of animal brains at several time points has failed to reveal any evidence of classical injury responses which might be responsible for preservation of basal forebrain neurons. These results contradict the theory that mature basal forebrain cholinergic neurons are critically dependent on the availability of target-derived neurotrophic factors and are therefore unlikely to be the major etiological factor in basal forebrain neuronal degeneration characteristic of Alzheimer's disease.


Assuntos
Acetilcolina/fisiologia , Envelhecimento/fisiologia , Córtex Cerebral/anatomia & histologia , Hipocampo/anatomia & histologia , Acetato de Metilazoximetanol/toxicidade , Neurônios/patologia , Prosencéfalo/anatomia & histologia , Doença de Alzheimer/patologia , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Feto/efeitos dos fármacos , Idade Gestacional , Proteína Glial Fibrilar Ácida/análise , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Gravidez , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Ratos , Ratos Endogâmicos
18.
Exp Neurol ; 117(2): 139-50, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1354164

RESUMO

A significant reduction in the activity of cholinergic enzymes in the neocortex is one of the characteristic neurochemical abnormalities in Alzheimer's disease. The withdrawal of cholinergic innervation is thought to be due to atrophy and degeneration of the cholinergic neurons of the basal forebrain, postulated to occur as a consequence of the loss of postsynaptic target neurons and trophic factors synthesized by these target cells. To directly test the dependence of basal forebrain cholinergic innervation on the presence of target neurons, pregnant rats were administered moderate doses of methylazoxymethanol acetate on Gestational Days 14 and 15. This results in a 40-70% reduction of cortical neurons in offspring of treated dams, but has no significant effect on the genesis of basal forebrain cholinergic neurons. In this paper, neurochemical analysis of cholinergic enzymes (ChAT and AchE) in 2-month-old offspring reveals that the basal forebrain innervates the hypocellular cortex in apparently normal fashion, despite the loss of target neurons. The cholinergic innervation of basal forebrain target regions was examined at various times through 20 months of age and was found to retain the initial high levels of enzymatic activity, without any evidence of loss of cholinergic innervation. The preservation of cholinergic innervation over 20 months despite the massive loss of target neurons contradicts the theory of dependence of basal forebrain cholinergic neurons on target-derived trophic support. These results suggest that the degeneration of basal forebrain cholinergic neurons in Alzheimer's disease is due to phenomena more complex than a reduction in the availability of trophic factors.


Assuntos
Acetilcolinesterase/metabolismo , Envelhecimento/fisiologia , Encéfalo/anatomia & histologia , Córtex Cerebral/enzimologia , Colina O-Acetiltransferase/metabolismo , Acetato de Metilazoximetanol/toxicidade , Neurônios/enzimologia , Prosencéfalo/enzimologia , Somatostatina/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Modelos Animais de Doenças , Feminino , Feto/efeitos dos fármacos , Idade Gestacional , Neurônios/efeitos dos fármacos , Neurônios/patologia , Gravidez , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Ratos , Ratos Endogâmicos
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