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1.
J Prev Alzheimers Dis ; 4(4): 236-241, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29181488

RESUMO

Tau neurofibrillary tangles are found in the brains of patients suffering from Alzheimer's disease and other tauopathies. The progressive spreading of tau pathology from one brain region to the next is believed to be caused by extracellular transsynaptic transmission of misfolded tau between neurons. Preclinical studies have shown that antibodies against tau can prevent this transfer of misfolded tau between cells. Thus, antibodies against tau have the potential to stop or slow the progression of tau pathology observed in human tauopathies. To test this hypothesis, a humanized anti-tau antibody (ABBV-8E12) was developed and a phase 1 clinical trial of this antibody has been completed. The double-blind, placebo-controlled phase 1 study tested single doses of ABBV-8E12 ranging from 2.5 to 50 mg/kg in 30 patients with progressive supranuclear palsy (PSP). ABBV-8E12 was found to have an acceptable safety profile with no clinically concerning trends in the number or severity of adverse events between the placebo and dosed groups. Pharmacokinetic modelling showed that the antibody has a plasma half-life and cerebrospinal fluid:plasma ratio consistent with other humanized antibodies, and there were no signs of immunogenicity against ABBV-8E12. Based on the acceptable safety and tolerability profile of single doses of ABBV-8E12, AbbVie is currently enrolling patients into two phase 2 clinical trials to assess efficacy and safety of multiple doses of ABBV-8E12 in patients with early Alzheimer's disease or PSP.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Tauopatias/terapia , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Método Duplo-Cego , Avaliação Pré-Clínica de Medicamentos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacocinética , Imunoterapia , Modelos Biológicos , Tauopatias/sangue , Tauopatias/líquido cefalorraquidiano
2.
Clin Pharmacol Ther ; 98(5): 469-71, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26250900

RESUMO

Alzheimer disease (AD) is the most common cause of dementia and is characterized by the aggregation and accumulation of two proteins in the brain, amyloid-ß (Aß) and tau. Aß and tau begin to buildup 15-20 years before the clinical onset of AD dementia. Increasing evidence suggests that preventing or decreasing the amount of aggregated forms of both Aß and tau in the brain can serve as potential disease-modifying treatments for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Descoberta de Drogas/métodos , Pensamento , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Imunoterapia/métodos , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
3.
Neurology ; 78(10): 709-19, 2012 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-22357717

RESUMO

OBJECTIVE: Measures of neuronal damage/dysfunction are likely good surrogates for disease progression in Alzheimer disease (AD). CSF markers of neuronal injury may offer utility in predicting disease progression and guiding prognostic and outcome assessments in therapeutic trials. Visinin-like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. We here investigate the utility of VILIP-1 and VILIP-1/Aß42 in predicting rates of cognitive decline in early AD. METHODS: Individuals with a clinical diagnosis of very mild or mild AD (n = 60) and baseline CSF measures of VILIP-1, tau, p-tau181, and Aß42 were followed longitudinally for an average of 2.6 years. Annual assessments included the Clinical Dementia Rating (CDR), CDR-sum of boxes (CDR-SB), and global composite scores. Mixed linear models assessed the ability of CSF biomarker measures to predict rates of cognitive decline over time. RESULTS: Baseline CSF VILIP-1 and VILIP-1/Aß42 levels predicted rates of future decline in CDR-SB and global composite scores over the follow-up period. Individuals with CSF VILIP-1 ≥560 pg/mL (corresponding to the upper tercile) progressed much more rapidly in CDR-SB (1.61 boxes/year; p = 0.0077) and global scores (-0.53 points/year; p = 0.0002) than individuals with lower values (0.85 boxes/year and -0.15 points/year, respectively) over the follow-up period. CSF tau, p-tau181, tau/Aß42, and p-tau181/Aß42 also predicted more rapid cognitive decline in CDR-SB and global scores over time. CONCLUSION: These findings suggest that CSF VILIP-1 and VILIP-1/Aß42 predict rates of global cognitive decline similarly to tau and tau/Aß42, and may be useful CSF surrogates for neurodegeneration in early AD.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Progressão da Doença , Neurocalcina/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Cognição , Transtornos Cognitivos/líquido cefalorraquidiano , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas tau/líquido cefalorraquidiano
4.
Neurology ; 76(6): 501-10, 2011 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-21228296

RESUMO

OBJECTIVE: To investigate factors, including cognitive and brain reserve, which may independently predict prevalent and incident dementia of the Alzheimer type (DAT) and to determine whether inclusion of identified factors increases the predictive accuracy of the CSF biomarkers Aß(42), tau, ptau(181), tau/Aß(42), and ptau(181)/Aß(42). METHODS: Logistic regression identified variables that predicted prevalent DAT when considered together with each CSF biomarker in a cross-sectional sample of 201 participants with normal cognition and 46 with DAT. The area under the receiver operating characteristic curve (AUC) from the resulting model was compared with the AUC generated using the biomarker alone. In a second sample with normal cognition at baseline and longitudinal data available (n = 213), Cox proportional hazards models identified variables that predicted incident DAT together with each biomarker, and the models' concordance probability estimate (CPE), which was compared to the CPE generated using the biomarker alone. RESULTS: APOE genotype including an ε4 allele, male gender, and smaller normalized whole brain volumes (nWBV) were cross-sectionally associated with DAT when considered together with every biomarker. In the longitudinal sample (mean follow-up = 3.2 years), 14 participants (6.6%) developed DAT. Older age predicted a faster time to DAT in every model, and greater education predicted a slower time in 4 of 5 models. Inclusion of ancillary variables resulted in better cross-sectional prediction of DAT for all biomarkers (p < 0.0021), and better longitudinal prediction for 4 of 5 biomarkers (p < 0.0022). CONCLUSIONS: The predictive accuracy of CSF biomarkers is improved by including age, education, and nWBV in analyses.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Apolipoproteína E4/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Feminino , Seguimentos , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Proteínas tau/líquido cefalorraquidiano
5.
Neurology ; 75(2): 111-5, 2010 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-20534887

RESUMO

OBJECTIVES: Diagnostic challenges exist for differentiating HIV dementia from Alzheimer disease (AD) in older HIV-infected (HIV+) individuals. Similar abnormalities in brain amyloid-beta42 (Alphabeta42) metabolism may be involved in HIV-associated neuropathology and AD. We evaluated the amyloid-binding agent (11)C-Pittsburgh compound B ((11)C-PiB), a biomarker for Alphabeta42 deposition, in cognitively unimpaired HIV+ (n = 10) participants and matched community controls without dementia (n = 20). METHODS: In this case-control study, all participants had an (11)C-PiB scan within 2 years of concomitant CSF studies and neuropsychometric testing. Statistical differences between HIV+ and community controls for demographic and clinical values were assessed by chi(2) tests. Participants were further divided into either low (<500 pg/mL) or normal (>or=500 pg/mL) CSF Alphabeta42 groups with Student t tests performed to determine if regional differences in fibrillar amyloid plaque deposition varied with CSF Alphabeta42. RESULTS: Regardless of CSF Alphabeta42 level, none of the HIV+ participants had fibrillar amyloid plaques as assessed by increased (11)C-PiB mean cortical binding potential (MCBP) or binding potential within 4 cortical regions. In contrast, some community controls with low CSF Alphabeta42 (<500 pg/mL) had high (11)C-PiB MCBP with elevated binding potentials (>0.18 arbitrary units) within cortical regions. CONCLUSIONS: Cognitively unimpaired HIV+ participants, even with low CSF Alphabeta42 (<500 pg/mL), do not have (11)C-PiB parameters suggesting brain fibrillar amyloid deposition. The dissimilarity between unimpaired HIV+ and preclinical AD may reflect differences in Abeta42 production and/or formation of diffuse plaques. Future longitudinal studies of HIV+ participants with low CSF Abeta42 and normal (11)C-PiB are required.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Benzotiazóis/metabolismo , Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Infecções por HIV/metabolismo , Adulto , Análise de Variância , Compostos de Anilina , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Radioisótopos de Carbono , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Transtornos Cognitivos/diagnóstico por imagem , Feminino , HIV , Infecções por HIV/diagnóstico por imagem , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Cintilografia , Tiazóis
6.
Brain Behav Immun ; 24(5): 759-67, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19945527

RESUMO

Cerebral periventricular white matter injury stands as a leading cause of cognitive, behavioral and motor impairment in preterm infants. There is epidemiological and histopathological evidence demonstrating the role of prenatal or neonatal inflammation in brain injury in preterm infants. In order to define the effect of an inflammatory insult in the developing brain on magnetic resonance (MR) imaging, we obtained high resolution conventional and diffusion MR images of the brain of rat pups after an inflammatory injury. Rat pups were subjected on postnatal day 5 (P5) to a stereotaxic injection of lipopolysaccharide in the corpus callosum and then imaged at 11.7 T on days 0, 2 and 4 following the injury. They were subsequently sacrificed for immunohistochemistry. Diffusion tensor imaging (DTI) acquired at high spatial resolution showed an initial reduction of the apparent diffusion coefficient (ADC) in the white matter. This was followed by an increase in ADC value and in T2 relaxation time constant in the white matter, with an associated increase of radial diffusivity of the corpus callosum, and a 10-fold increase in ventricular size. On histology, these MR changes corresponded to widespread astrogliosis, and decreased proportion of the section areas containing cresyl violet positive stain. The increase in radial diffusivity, typically attributed to myelin loss, occurred in this case despite the absence of myelin at this developmental stage.


Assuntos
Lesões Encefálicas/patologia , Encéfalo/patologia , Animais , Animais Recém-Nascidos , Anisotropia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Inflamação/patologia , Imageamento por Ressonância Magnética , Masculino , Fibras Nervosas Mielinizadas/patologia , Ratos , Ratos Sprague-Dawley , Estatísticas não Paramétricas
7.
Neurology ; 73(23): 1982-7, 2009 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-19907013

RESUMO

BACKGROUND: HIV-associated neurologic disorders (HAND) continue to develop in many patients with HIV. CSF amyloid measurements in HAND have been reported to be similar to those in dementia of the Alzheimer type (DAT). Confirmatory evaluation of this finding in carefully evaluated subjects is needed. METHODS: CSF specimens were obtained from subjects clinically categorized with normal cognition from the general population, HIV+ subjects with normal cognition, HIV+ subjects with impaired cognition, or presumed HIV- subjects with mild DAT. CSF measurements of beta-amyloid((1-42)) (Abeta42), beta-amyloid((1-40)) (Abeta40), total tau (t-tau), and phosphorylated tau (p-tau181) were performed. RESULTS: CSF Abeta42 measured in 49 HAND subjects had a median level of 501 pg/mL, which was lower than that of 50 controls of similar age who had median of 686 pg/mL (p < 0.0001) or 21 HIV+ subjects without cognitive impairment who had median of 716 pg/mL (p < 0.003). HAND subjects had similar CSF Abeta42 to 68 subjects with mild DAT. There was no difference of CSF Abeta40 between the groups. Tau and p-tau181 was elevated in DAT, but slightly lower than control in both HIV+ groups. CONCLUSIONS: beta-Amyloid((1-42)) (Abeta42) measurements in CSF of cognitively impaired patients with HIV are similar to those in patients with mild dementia of the Alzheimer type (DAT). Normal or slightly depressed CSF tau and p-tau181 measurements distinguish these patients with HIV-associated neurologic disorders (HAND) from patients with DAT. Further evaluation of amyloid metabolism in patients with HIV cognitive disorder is needed to understand the implications of depressed CSF Abeta42 in the setting of HAND.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Infecções por HIV/líquido cefalorraquidiano , Infecções por HIV/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Infecções por HIV/diagnóstico , Humanos , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/líquido cefalorraquidiano , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/diagnóstico , Proteínas tau/líquido cefalorraquidiano
8.
Eur J Neurosci ; 30(4): 662-70, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19686474

RESUMO

During avian vocal learning, birds memorize conspecific song patterns and then use auditory feedback to match their vocal output to this acquired template. Some models of song learning posit that during tutoring, conspecific visual, social and/or auditory cues activate neuromodulatory systems that encourage acquisition of the tutor's song and attach incentive value to that specific acoustic pattern. This hypothesis predicts that stimuli experienced during social tutoring activate cell populations capable of signaling reward. Using immunocytochemistry for the protein product of the immediate early gene c-Fos, we found that brief exposure of juvenile male zebra finches to a live familiar male tutor increased the density of Fos+ cells within two brain regions implicated in reward processing: the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). This activation of Fos appears to involve both dopaminergic and non-dopaminergic VTA/SNc neurons. Intriguingly, a familiar tutor was more effective than a novel tutor in stimulating Fos expression within these regions. In the periaqueductal gray, a dopamine-enriched cell population that has been implicated in emotional processing, Fos labeling also was increased after tutoring, with a familiar tutor again being more effective than a novel conspecific. As several neural regions implicated in song acquisition receive strong dopaminergic projections from these midbrain nuclei, their activation in conjunction with hearing the tutor's song could help to establish sensory representations that later guide motor sequence learning.


Assuntos
Dopamina/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Substância Negra/metabolismo , Área Tegmentar Ventral/metabolismo , Vocalização Animal/fisiologia , Estimulação Acústica , Análise de Variância , Animais , Contagem de Células , Feminino , Tentilhões , Imuno-Histoquímica , Aprendizagem/fisiologia , Masculino , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/metabolismo , Substância Cinzenta Periaquedutal/fisiologia , Reconhecimento Psicológico , Substância Negra/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/fisiologia
9.
Proc Natl Acad Sci U S A ; 106(29): 12145-50, 2009 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-19581601

RESUMO

A number of distinct beta-amyloid (Abeta) variants or multimers have been implicated in Alzheimer's disease (AD), and antibodies recognizing such peptides are in clinical trials. Humans have natural Abeta-specific antibodies, but their diversity, abundance, and function in the general population remain largely unknown. Here, we demonstrate with peptide microarrays the presence of natural antibodies against known toxic Abeta and amyloidogenic non-Abeta species in plasma samples and cerebrospinal fluid of AD patients and healthy controls aged 21-89 years. Antibody reactivity was most prominent against oligomeric assemblies of Abeta and pyroglutamate or oxidized residues, and IgGs specific for oligomeric preparations of Abeta1-42 in particular declined with age and advancing AD. Most individuals showed unexpected antibody reactivities against peptides unique to autosomal dominant forms of dementia (mutant Abeta, ABri, ADan) and IgGs isolated from plasma of AD patients or healthy controls protected primary neurons from Abeta toxicity. Aged vervets showed similar patterns of plasma IgG antibodies against amyloid peptides, and after immunization with Abeta the monkeys developed high titers not only against Abeta peptides but also against ABri and ADan peptides. Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides. If a therapeutic benefit of Abeta antibodies can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD.


Assuntos
Envelhecimento/imunologia , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/imunologia , Anticorpos/imunologia , Fármacos Neuroprotetores/imunologia , Peptídeos/imunologia , Envelhecimento/efeitos dos fármacos , Doença de Alzheimer/sangue , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Citoproteção/efeitos dos fármacos , Demência/complicações , Demência/imunologia , Progressão da Doença , Genes Dominantes , Imunização , Imunoglobulina G/sangue , Camundongos , Peso Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Peptídeos/química , Primatas/imunologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estrutura Quaternária de Proteína
10.
AJNR Am J Neuroradiol ; 29(1): 18-22, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17925367

RESUMO

Histologically identified intracellular and extracellular inclusions and structures often provide a tissue diagnosis of a specific disease process. Moreover, these deposits may provide clues about the pathogenesis of the disease in which they are found. Two distinctive structures seen within the brains of patients clinically diagnosed with dementia of the Alzheimer type are extracellular plaques and intracellular neurofibrillary tangles. The purpose of this report is to review the significance of plaques and neurofibrillary tangles in the context of Alzheimer disease.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Modelos Neurológicos , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/diagnóstico por imagem , Humanos , Modelos Anatômicos , Emaranhados Neurofibrilares/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Radiografia
11.
Exp Neurol ; 205(1): 116-31, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17368446

RESUMO

Traumatic axonal injury (TAI) is thought to be a major contributor to cognitive dysfunction following traumatic brain injury (TBI), however TAI is difficult to diagnose or characterize non-invasively. Diffusion tensor imaging (DTI) has shown promise in detecting TAI, but direct comparison to histologically-confirmed axonal injury has not been performed. In the current study, mice were imaged with DTI, subjected to a moderate cortical controlled impact injury, and re-imaged 4-6 h and 24 h post-injury. Axonal injury was detected by amyloid beta precursor protein (APP) and neurofilament immunohistochemistry in pericontusional white matter tracts. The severity of axonal injury was quantified using stereological methods from APP stained histological sections. Two DTI parameters--axial diffusivity and relative anisotropy--were significantly reduced in the injured, pericontusional corpus callosum and external capsule, while no significant changes were seen with conventional MRI in these regions. The contusion was easily detectable on all MRI sequences. Significant correlations were found between changes in relative anisotropy and the density of APP stained axons across mice and across subregions spanning the spatial gradient of injury. The predictive value of DTI was tested using a region with DTI changes (hippocampal commissure) and a region without DTI changes (anterior commissure). Consistent with DTI predictions, there was histological detection of axonal injury in the hippocampal commissure and none in the anterior commissure. These results demonstrate that DTI is able to detect axonal injury, and support the hypothesis that DTI may be more sensitive than conventional imaging methods for this purpose.


Assuntos
Axônios/patologia , Lesões Encefálicas/diagnóstico , Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Anisotropia , Axônios/metabolismo , Encéfalo/metabolismo , Lesões Encefálicas/metabolismo , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Feminino , Hipocampo/patologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos , Proteínas de Neurofilamentos/metabolismo , Valor Preditivo dos Testes , Índice de Gravidade de Doença , Distribuição Tecidual
12.
Neurology ; 66(4): 602-4, 2006 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-16505324

RESUMO

LY450139 dihydrate, a gamma-secretase inhibitor, was studied in a randomized, controlled trial of 70 patients with Alzheimer disease. Subjects were given 30 mg for 1 week followed by 40 mg for 5 weeks. Treatment was well tolerated. Abeta(1-40) in plasma decreased by 38.2%; in CSF, Abeta(1-40) decreased by 4.42 +/- 9.55% (p = not significant). Higher drug doses may result in additional decreases in plasma Abeta concentrations and a measurable decrease in CSF Abeta.


Assuntos
Alanina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Azepinas/uso terapêutico , Endopeptidases/metabolismo , Alanina/farmacocinética , Alanina/uso terapêutico , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Azepinas/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/uso terapêutico , Humanos , Placebos
13.
Neuroscience ; 122(2): 305-15, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-14614898

RESUMO

Dendritic spines are postsynaptic sites of excitatory input in the mammalian nervous system. Apolipoprotein (apo) E participates in the transport of plasma lipids and in the redistribution of lipids among cells. A role for apoE is implicated in regeneration of synaptic circuitry after neural injury. The apoE4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. ApoE isoforms are suggested to have differential effects on neuronal repair mechanisms. In vitro studies have demonstrated the neurotrophic properties of apoE3 on neurite outgrowth. We have investigated the influence of apoE genotype on neuronal cell dendritic spine density in mice and in human postmortem tissue. In order to compare the morphology of neurons developing under different apoE conditions, gene gun labeling studies of dendritic spines of dentate gyrus (DG) granule cells of the hippocampus were carried out in wild-type (WT), human apoE3, human apoE4 expressing transgenic mice and apoE knockout (KO) mice; the same dendritic spine parameters were also assessed in human postmortem DG from individuals with and without the apoE4 gene. Quantitative analysis of dendritic spine length, morphology, and number was carried out on these mice at 3 weeks, 1 and 2 years of age. Human apoE3 and WT mice had a higher density of dendritic spines than human E4 and apoE KO mice in the 1 and 2 year age groups (P<0.0001), while at 3 weeks there were no differences between the groups. These age dependent differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of dementia in aged individuals with the apoE4 allele. Significantly in human brain, apoE4 dose correlated inversely with dendritic spine density of DG neurons cell in the hippocampus of both AD (P=0.0008) and aged normal controls (P=0.0015). Our findings provide one potential explanation for the increased cognitive decline seen in aged and AD patients expressing apoE4.


Assuntos
Doença de Alzheimer/patologia , Apolipoproteínas E/biossíntese , Apolipoproteínas E/fisiologia , Dendritos/metabolismo , Dendritos/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E3 , Apolipoproteína E4 , Apolipoproteínas E/genética , Dendritos/genética , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia
14.
Cell Death Differ ; 10(10): 1148-55, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14502238

RESUMO

A single episode of ethanol intoxication triggers widespread apoptotic neurodegeneration in the infant rat or mouse brain. The cell death process occurs over a 6-16 h period following ethanol administration, is accompanied by a robust display of caspase-3 enzyme activation, and meets ultrastructural criteria for apoptosis. Two apoptotic pathways (intrinsic and extrinsic) have been described, either of which may culminate in the activation of caspase-3. The intrinsic pathway is regulated by Bax and Bcl-XL and involves Bax-induced mitochondrial dysfunction and release of cytochrome c as antecedent events leading to caspase-3 activation. Activation of caspase-8 is a key event preceding caspase-3 activation in the extrinsic pathway. In the present study, following ethanol administration to infant mice, we found no change in activated caspase-8, which suggests that the extrinsic pathway is not involved in ethanol-induced apoptosis. We also found that ethanol triggers robust caspase-3 activation and apoptotic neurodegeneration in C57BL/6 wildtype mice, but induces neither phenomenon in homozygous Bax-deficient mice. Therefore, it appears that ethanol-induced neuroapoptosis is an intrinsic pathway-mediated phenomenon involving Bax-induced disruption of mitochondrial membranes and cytochrome c release as early events leading to caspase-3 activation.


Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Etanol/farmacologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2 , Proteínas Proto-Oncogênicas/fisiologia , Animais , Núcleos Anteriores do Tálamo/efeitos dos fármacos , Núcleos Anteriores do Tálamo/patologia , Western Blotting , Encéfalo/patologia , Química Encefálica/efeitos dos fármacos , Caspase 3 , Caspase 8 , Caspases/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Citocromos c/análise , Etanol/sangue , Genótipo , Heterozigoto , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Proteínas Proto-Oncogênicas/genética , Espectrina/análise , Fatores de Tempo , Regulação para Cima , Proteína X Associada a bcl-2
15.
Stroke ; 34(1): 207-13, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12511776

RESUMO

BACKGROUND AND PURPOSE: Different strategies for neuroprotection of neonatal stroke may be required because the developing brain responds differently to hypoxia-ischemia than the mature brain. This study was designed to determine the role of caspase-dependent injury in the pathophysiology of pure focal cerebral ischemia in the immature brain. METHODS: Postnatal day 7 rats were subjected to permanent or transient middle cerebral artery (MCA) occlusion. Diffusion-weighted MRI was used during occlusion to noninvasively map the evolving ischemic core. The time course of caspase-3 activation in ischemic brain tissue was determined with the use of an Asp-Glu-Val-Asp-aminomethylcoumarin cleavage assay. The anatomy of caspase-3 activation in the ischemic core and penumbra was mapped immunohistochemically with an anti-activated caspase-3 antibody in coronal sections that matched the imaging planes on diffusion-weighted MRI. RESULTS: A marked increase in caspase-3 activity occurred within 24 hours of reperfusion after transient MCA occlusion. In contrast, caspase-3 activity remained significantly lower within 24 hours of permanent MCA occlusion. Cells with activated caspase-3 were prominent in the penumbra beginning at 3 hours after reperfusion, while a more delayed but marked caspase-3 activation was observed in the ischemic core by 24 hours after reperfusion. CONCLUSIONS: In the neonate, caspase-3 activation is likely to contribute substantially to cell death not only in the penumbra but also in the core after ischemia with reperfusion. Furthermore, persistent perfusion deficits result in less caspase-3 activation and appear to favor caspase-independent injury.


Assuntos
Isquemia Encefálica/enzimologia , Caspases/metabolismo , Córtex Cerebral/enzimologia , Traumatismo por Reperfusão/enzimologia , Acidente Vascular Cerebral/complicações , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Isquemia Encefálica/etiologia , Isquemia Encefálica/patologia , Caspase 3 , Circulação Cerebrovascular , Imagem de Difusão por Ressonância Magnética , Ativação Enzimática , Infarto da Artéria Cerebral Média/complicações , Cinética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia
17.
Mol Interv ; 2(6): 363-75, 339, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14993413

RESUMO

Despite important inroads into the molecular pathology of Alzheimer disease, effective long-term treatment for the condition remains elusive. Among the many gene products that are recognized as factors in the disease is apolipoprotein ( (apoE). The risk that specific isoforms of apoE pose with regard to Alzheimer Disease clearly varies, and so the roles that apoE plays in the brain will be crucial to a full understanding of the disease and to efforts to develop effective therapies.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Amiloide/metabolismo , Apolipoproteínas E/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Apolipoproteínas E/genética , Sistema Nervoso Central/metabolismo , Predisposição Genética para Doença , Humanos , Camundongos
18.
J Neurosci Res ; 66(5): 866-72, 2001 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-11746413

RESUMO

In cerebral gray matter, ATP concentration is closely maintained despite rapid, large increases in turnover and low substrate reserves. As seen in vivo by (31)P nuclear magnetic resonance (NMR) spectroscopy, brain ATP is stable early in seizures, a state of high energy demand, and in mild hypoxia, a state of substrate deficiency. Like other tissues with high and variable ATP turnover, cerebral gray matter has high phosphocreatine (PCr) concentration and both cytosolic and mitochondrial creatine kinase (UbMi-CK) isoenzymes. To understand the physiology of brain creatine kinases, we used (31)P NMR to study PCr and ATP regulation during seizures and hypoxia in mice with targeted deletion of the UbMi-CK gene. The baseline CK reaction rate constant (k) was higher in mutants than wild-types. During seizures, PCr and ATP decreased in mutants but not in wild-types. The k-value for the CK catalyzed reaction rate increased in wild-types but not in the mutants. Hypoxic mutants and wild-types showed similar PCr losses and stable ATP. During recovery from hypoxia, brain PCr and ATP concentrations returned to baseline in wild-types but were 20% higher than baseline in the mutants. We propose that UbMi-CK couples ATP turnover to the CK catalyzed reaction rate and regulates ATP concentration when synthesis is increased.


Assuntos
Trifosfato de Adenosina/metabolismo , Encéfalo/enzimologia , Creatina Quinase/deficiência , Regulação Enzimológica da Expressão Gênica/genética , Isoenzimas/deficiência , Mitocôndrias/enzimologia , Fosfocreatina/metabolismo , Hidrolases Anidrido Ácido/metabolismo , Animais , Convulsivantes/farmacologia , Creatina Quinase/genética , Creatina Quinase Mitocondrial , Hipóxia Encefálica/enzimologia , Hipóxia Encefálica/fisiopatologia , Imuno-Histoquímica , Isoenzimas/genética , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Knockout , Nucleosídeo-Trifosfatase , Pentilenotetrazol/farmacologia , Convulsões/enzimologia , Convulsões/fisiopatologia , Frações Subcelulares/metabolismo
20.
Neurochem Int ; 39(5-6): 415-25, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11578777

RESUMO

The varepsilon4 allele of apolipoprotein E (apoE) is a genetic risk factor for Alzheimer's disease (AD). In order to gain a better understanding of the molecular mechanisms by which apoE and possibly other apolipoproteins produced in the central nervous system (CNS) influence AD pathogenesis, we have purified and characterized the two most abundant apolipoproteins produced in the CNS, apoE and apoJ. We purified apoE and apoJ from primary cultures of mouse astrocytes, which were derived from transgenic mice expressing human apoE isoforms in the absence of mouse apoE. Utilizing antibody affinity columns, we were able to purify both human apoE3 and apoE4, as well as mouse apoJ-containing lipoproteins. Astrocyte-secreted human apoE was present in high density-like lipoproteins of three predominant sizes ranging from 8 to 15 nm in diameter. Mouse apoJ was in particles between 10 and 17 nm in diameter with a peak size range of approximately 11 nm. ApoE and apoJ were in distinct lipoproteins. Utilization of quick-freeze, deep-etch electron microscopy revealed the apoE particles were discs while the apoJ particles were smaller and more irregular in appearance. The lipid composition of apoE particles was very different from those containing apoJ. ApoE-particles contained a similar mass of apoE and lipid, with cholesterol and phospholipid being about equal in mass per particle. ApoJ-particles were relatively lipid poor (three parts protein, one part lipid), with phospholipids being much more abundant than cholesterol. Detailed characterization of phospholipid composition by electrospray ionization mass spectrometry analysis revealed ethanolamine glycerophospholipids to be the most abundant phospholipid present in both apoE and apoJ particles. Analysis of cerebrospinal fluid from apoE3 and apoE4 transgenic mice revealed that human and mouse apoE were in particles the same size as those secreted by astrocytes. Further use of physiological preparations of CNS-derived lipoproteins may allow for a detailed understanding of the role of these molecules in the normal brain and in diseases such as AD.


Assuntos
Apolipoproteínas E/análise , Astrócitos/metabolismo , Glicoproteínas/análise , Lipoproteínas/química , Lipoproteínas/isolamento & purificação , Chaperonas Moleculares/análise , Animais , Apolipoproteínas E/líquido cefalorraquidiano , Apolipoproteínas E/química , Células Cultivadas , Clusterina , Glicoproteínas/líquido cefalorraquidiano , Glicoproteínas/química , Humanos , Lipídeos/análise , Lipoproteínas HDL/química , Camundongos , Camundongos Transgênicos , Chaperonas Moleculares/líquido cefalorraquidiano , Chaperonas Moleculares/química , Tamanho da Partícula , Fosfolipídeos/análise , Valores de Referência
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