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1.
AIDS Res Hum Retroviruses ; 33(9): 905-918, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28398068

RESUMO

HIV infects and destroys CD4+ T cells leading to a compromised immune system. In a double-blinded study, a group of HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 were given either an empty liposomal supplement or a liposomal glutathione (L-GSH) supplement to take over a 3-month period. Baseline measurements in HIV-positive subjects show a significant decrease in levels of interleukin (IL)-12, IL-2, and interferon (IFN)-γ, along with a substantial increase in the levels of IL-6, IL-10, transforming growth factor (TGF)-ß, and free radicals, compared to healthy individuals. Supplementation of HIV-positive subjects with L-GSH for 3 months resulted in a notable increase in the levels of IL-12, IL-2, and IFN-γ, with a concomitant decrease in the levels of IL-6, IL-10, and free radicals, and stabilization in the levels of TGF-ß, IL-1, and IL-17, compared to their placebo counterparts. Levels of free radicals in CD4+ T cells stabilized, while GSH levels increased in the treatment group. Those in the placebo group showed no significant difference throughout the study. In summary, supplementation with L-GSH in HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 can help restore redox homeostasis and cytokine balance, therefore aiding the immune system to control opportunistic infections.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Infecções por HIV/imunologia , Adulto , Idoso , Contagem de Linfócito CD4/métodos , Feminino , Humanos , Interferon gama/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta/imunologia
2.
Data Brief ; 8: 1044-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27508262

RESUMO

Our most recent data indicate differences in the levels of pro-inflammatory cytokines (IL-1ß, IL-17, and IL-6) and malondialdehyde (MDA), a stable end-product of lipid peroxidation in the plasma samples between HIV positive individuals with low CD4 T cell counts <200 mm(3) and HIV positive individuals with CD4 T cell counts between 200 and 300 mm(3) (ee). The data lend support and provide valuable correlation between CD4 T cell counts and the levels of inflammatory cytokines in HIV positive individuals.

3.
BBA Clin ; 6: 38-44, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27335804

RESUMO

HIV-1 positive individuals are at high risk for susceptibility to both pulmonary tuberculosis (TB) and extra-pulmonary TB, including TB meningitis (TBM) which is an extreme form of TB. The goals of this study are to determine the mechanisms responsible for compromised levels of glutathione (GSH) in the brain tissue samples derived from HIV-1-infected individuals and individuals with Alzheimer's disease (AD), investigate the possible underlying mechanisms responsible for GSH deficiency in these pathological conditions, and establish a link between GSH levels and pathophysiology of the disease processes. We demonstrated in the autopsied human brain tissues that the levels of total and reduced forms of GSH were significantly compromised in HIV-1 infected individuals compared to in healthy subjects and individuals with AD. Brain tissue samples derived from HIV-1-positive individuals had substantially higher levels of free radicals than that derived from healthy and AD individuals. Enzymes that are responsible for the de novo synthesis of GSH such as γ-glutamate cysteine-ligase catalytic subunit (GCLC-rate limiting step enzyme) and glutathione synthetase (GSS-enzyme involved in the second step reaction) were significantly decreased in the brain tissue samples derived from HIV-1-positive individuals with low CD4 + T-cells (< 200 cells/mm(3)) compared to healthy and AD individuals. Levels of glutathione reductase (GSR) were also decreased in the brain tissue samples derived from HIV-1 infected individuals. Overall, our findings demonstrate causes for GSH deficiency in the brain tissue from HIV-1 infected individuals explaining the possible reasons for increased susceptibility to the most severe form of extra-pulmonary TB, TBM.

4.
J Interferon Cytokine Res ; 35(11): 875-87, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26133750

RESUMO

Cytokines are signaling biomolecules that serve as key regulators of our immune system. CD4(+) T-cells can be grouped into 2 major categories based on their cytokine profile: T-helper 1 (TH1) subset and T-helper 2 (TH2) subset. Protective immunity against HIV infection requires TH1-directed CD4 T-cell responses, mediated by cytokines, such as interleukin-1ß (IL-1ß), IL-12, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). Cytokines released by the TH1 subset of CD4 T-cells are considered important for mediating effective immune responses against intracellular pathogens such as Mycobacterium tuberculosis (M. tb). Oxidative stress and redox imbalance that occur during HIV infection often lead to inappropriate immune responses. Glutathione (GSH) is an antioxidant present in nearly all cells and is recognized for its function in maintaining redox homeostasis. Our laboratory previously reported that individuals with HIV infection have lower levels of GSH. In this study, we report a link between lower levels of GSH and dysregulation of TH1- and TH2-associated cytokines in the plasma samples of HIV-positive subjects. Furthermore, we demonstrate that supplementing individuals with HIV infection for 13 weeks with liposomal GSH (lGSH) resulted in a significant increase in the levels of TH1 cytokines, IL-1ß, IL-12, IFN-γ, and TNF-α. lGSH supplementation in individuals with HIV infection also resulted in a substantial decrease in the levels of free radicals and immunosuppressive cytokines, IL-10 and TGF-ß, relative to those in a placebo-controlled cohort. Finally, we determined the effects of lGSH supplementation in improving the functions of immune cells to control M. tb infection by conducting in vitro assays using peripheral blood mononuclear cells collected from HIV-positive individuals at post-GSH supplementation. Our studies establish a correlation between low levels of GSH and increased susceptibility to M. tb infection through TH2-directed response, which may be relieved with lGSH supplementation enhancing the TH1 response.


Assuntos
Antioxidantes/uso terapêutico , Citocinas/biossíntese , Glutationa/uso terapêutico , Infecções por HIV/imunologia , Células Th1/imunologia , Tuberculose Pulmonar/imunologia , Adulto , Idoso , Contagem de Linfócito CD4 , Portadores de Fármacos/uso terapêutico , Infecções por HIV/complicações , Humanos , Interferon gama/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Interleucina-1beta/biossíntese , Lipossomos/uso terapêutico , Pessoa de Meia-Idade , Mycobacterium tuberculosis , Oxirredução , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/metabolismo , Células Th2/imunologia , Tuberculose Pulmonar/complicações , Fator de Necrose Tumoral alfa/biossíntese , Adulto Jovem
5.
PLoS One ; 10(3): e0118436, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25790445

RESUMO

Tuberculosis (TB) remains an eminent global burden with one third of the world's population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-ß), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection.


Assuntos
Citocinas/sangue , Complicações do Diabetes/microbiologia , Diabetes Mellitus Tipo 2/metabolismo , Glutationa/deficiência , Fator de Crescimento Transformador beta/sangue , Tuberculose/imunologia , Adulto , Western Blotting , Complicações do Diabetes/imunologia , Suscetibilidade a Doenças/imunologia , Citometria de Fluxo , Glutationa/sangue , Humanos , Immunoblotting , Interleucina-17/sangue , Interleucina-6/sangue , Macrófagos/metabolismo , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/sangue , Corantes de Rosanilina , Tuberculose/etiologia
6.
Neurosci Lett ; 560: 86-91, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24361548

RESUMO

Immunotherapeutic approaches reducing α-synuclein deposits may provide therapeutic benefit for Dementia with Lewy Bodies (DLB). Immunization with full-length human α-synuclein (hα-Syn) protein in a Parkinson's disease mouse model decreased the accumulation of the aggregated forms of this protein in neurons and reduced neurodegeneration. To enhance the immunogenicity of candidate vaccines and to avoid the risk of autoreactive anti-hα-Syn T-helper (Th) cell responses, we generated three peptide-based epitope vaccines composed of different B-cell epitopes of hα-Syn fused with a "non-self" Th epitope from tetanus toxin (P30). Immunization of mice with these epitope vaccines produced high titers of anti-hα-Syn antibodies that bound to Lewy bodies (LBs) and Lewy neurites (LNs) in brain tissue from DLB cases and induced robust Th cell responses to P30, but not to hα-Syn. Further development of these first generation epitope vaccines may facilitate induction of anti-hα-Syn immunotherapy without producing potentially harmful autoreactive Th cell responses.


Assuntos
Epitopos de Linfócito B/imunologia , Vacinas/imunologia , alfa-Sinucleína/imunologia , Animais , Formação de Anticorpos , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Epitopos de Linfócito B/genética , Estudos de Viabilidade , Feminino , Humanos , Corpos de Lewy/imunologia , Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/imunologia , Doença por Corpos de Lewy/patologia , Camundongos , Neuritos/imunologia , Neuritos/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Toxina Tetânica/genética , Vacinação , Vacinas/genética , alfa-Sinucleína/genética
7.
Brain Pathol ; 22(6): 826-33, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22486774

RESUMO

Like amyloid beta (Aß) oligomers, tau aggregates are increasingly recognized as potential key toxic intermediates in Alzheimer's disease (AD) and as therapeutic targets. P-tau co-localizes with Aß in cortical AD synapses and may contribute to synapse dysfunction and loss. Flow cytometry analysis of synaptosomes from AD compared with aged cognitively normal cortex demonstrates increased immunolabeling for three p-tau antibodies (AT8, PHF-1 and pS422), indicating phosphorylation at multiple tau epitopes. Sequential extraction experiments show increased soluble p-tau in AD synapses, but a sizable pool of p-tau requires detergent solubilization, suggesting endosomal/lysosomal localization. P-tau is co-localized with Aß in individual synaptosomes in dual labeling experiments, and flow cytometry sorting of Aß-positive synaptosomes from an AD case reveals a marked enrichment of p-tau aggregates. The p-tau enrichment, a 76-fold increase over the initial homogenate, is consistent with sequestration of p-tau in internal synaptic compartments. Western analysis of a series of AD and normal cases shows SDS-stable tau oligomers in the dimer/trimer size range in AD samples. These results indicate that widespread synaptic p-tau pathology accompanies Aß accumulations in surviving synaptic terminals, particularly in late-stage AD.


Assuntos
Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Sinapses/metabolismo , Sinapses/patologia , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Western Blotting , Córtex Cerebral/química , Citometria de Fluxo , Humanos , Fosforilação , Sinapses/química , Sinaptossomos/química , Sinaptossomos/metabolismo , Sinaptossomos/patologia , Proteínas tau/química
8.
J Neurotrauma ; 29(6): 1054-70, 2012 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-22017610

RESUMO

Dementia pugilistica (DP) is associated with chronic traumatic brain injury (CTBI), and leads to a "punch drunk" syndrome characterized by impairments in memory and executive function, behavioral changes, and motor signs. Microscopic features include the accumulation of neurofibrillary tangles (NFTs), beta-amyloid (Aß), and TAR DNA binding protein 43 (TDP-43) pathology. Here we describe detailed clinical and neuropathological data about a 55-year-old retired boxer (ApoE3/4), who presented with executive dysfunction and behavioral impairments. At autopsy, significant Aß pathology was seen, primarily in the form of diffuse plaques. Tau pathology was extensive and was determined to be of Braak and Braak stage VI. Frontal white matter showed evidence of glial tau inclusions (astrocytes and oligodendroglia). Cerebrovascular pathology was minimal with patchy amyloid angiopathy. Inflammation was another key feature, including microglial activation and significant C1q labeling of neurons, along with NFTs. TDP-43-positive pathology was also observed. Inflammation may be a key inciting as well as propagating feature of DP neuropathology.


Assuntos
Lesões Encefálicas/patologia , Demência/patologia , Lobo Frontal/patologia , Inflamação/patologia , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/metabolismo , Doença Crônica , Demência/etiologia , Demência/metabolismo , Lobo Frontal/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Corpos de Inclusão/patologia , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Placa Amiloide/metabolismo , Proteínas tau/metabolismo
9.
Acta Neuropathol ; 123(1): 39-52, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22020632

RESUMO

The apolipoprotein E4 allele (APOE4) contributes to Alzheimer's disease (AD) risk and APOE2 is protective, but the relevant cellular mechanisms are unknown. We have used flow cytometry analysis to measure apolipoprotein E (apoE) and amyloid beta peptide (Aß) levels in large populations of synaptic terminals from AD and aged cognitively normal controls, and demonstrate that modest but significant increases in soluble apoE levels accompany elevated Aß in AD cortical synapses and in an APP/PS1 rat model of AD. Dual labeling experiments document co-localization of apoE and Aß in individual synapses with concentration of Aß in a small population of apoE-positive synapses in both AD and controls. Consistent with a clearance role, the apoE level was higher in Aß-positive synapses in control cases. In aged targeted replacement mice expressing human apoE, apoE2/4 synaptic terminals demonstrated the highest level of apoE and the lowest level of Aß compared to apoE3/3 and apoE4/4 lines. In apoE2/4 terminals, the pattern of immunolabeling for apoE and Aß closely resembled the pattern in human control cases, and elevated apoE was accompanied by elevated free cholesterol in apoE2/4 synaptic terminals. These results are consistent with a role for APOE in Aß clearance in AD synapses, and suggest that optimal lipidation of apoE2 compared to E3 and E4 makes an important contribution to Aß clearance and synaptic function.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Colesterol/metabolismo , Terminações Pré-Sinápticas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Apolipoproteína E2/metabolismo , Apolipoproteína E3/metabolismo , Apolipoproteína E4/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Transgênicos
10.
PLoS One ; 6(9): e24652, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21931796

RESUMO

Lifestyle interventions such as diet, exercise, and cognitive training represent a quietly emerging revolution in the modern approach to counteracting age-related declines in brain health. Previous studies in our laboratory have shown that long-term dietary supplementation with antioxidants and mitochondrial cofactors (AOX) or behavioral enrichment with social, cognitive, and exercise components (ENR), can effectively improve cognitive performance and reduce brain pathology of aged canines, including oxidative damage and Aß accumulation. In this study, we build on and extend our previous findings by investigating if the interventions reduce caspase activation and ceramide accumulation in the aged frontal cortex, since caspase activation and ceramide accumulation are common convergence points for oxidative damage and Aß, among other factors associated with the aged and AD brain. Aged beagles were placed into one of four treatment groups: CON--control environment/control diet, AOX--control environment/antioxidant diet, ENR--enriched environment/control diet, AOX/ENR--enriched environment/antioxidant diet for 2.8 years. Following behavioral testing, brains were removed and frontal cortices were analyzed to monitor levels of active caspase 3, active caspase 9 and their respective cleavage products such as tau and semaphorin7a, and ceramides. Our results show that levels of activated caspase-3 were reduced by ENR and AOX interventions with the largest reduction occurring with combined AOX/ENR group. Further, reductions in caspase-3 correlated with reduced errors in a reversal learning task, which depends on frontal cortex function. In addition, animals treated with an AOX arm showed reduced numbers of cells expressing active caspase 9 or its cleavage product semaphorin 7A, while ENR (but not AOX) reduced ceramide levels. Overall, these data demonstrate that lifestyle interventions curtail activation of pro-degenerative pathways to improve cellular health and are the first to show that lifestyle interventions can regulate caspase pathways in a higher animal model of aging.


Assuntos
Envelhecimento/metabolismo , Encéfalo/metabolismo , Caspases/metabolismo , Suplementos Nutricionais , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/metabolismo , Encéfalo/fisiologia , Caspase 3/metabolismo , Caspase 9/metabolismo , Bovinos , Ceramidas/metabolismo , Feminino , Immunoblotting , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Semaforinas/metabolismo
11.
Neurobiol Dis ; 39(3): 301-10, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20451612

RESUMO

Previously we showed that anti-Abeta peptide immunotherapy significantly attenuated Alzheimer's-like amyloid deposition in the central nervous system of aged canines. In this report we have characterized the changes that occurred in the humoral immune response over 2.4years in canines immunized repeatedly with aggregated Abeta(1-42) (AN1792) formulated in alum adjuvant. We observed a rapid and robust induction of anti-Abeta antibody titers, which were associated with an anti-inflammatory T helper type 2 (Th2) response. The initial antibody response was against dominant linear epitope at the N-terminus region of the Abeta(1-42) peptide, which is identical to the one in humans and vervet monkeys. After multiple immunizations the antibody response drifted toward the elevation of antibodies that recognized conformational epitopes of assembled forms of Abeta and other types of amyloid. Our findings indicate that prolonged immunization results in distinctive temporal changes in antibody profiles, which may be important for other experimental and clinical settings.


Assuntos
Vacinas contra Alzheimer/administração & dosagem , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/imunologia , Formação de Anticorpos/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/prevenção & controle , Análise de Variância , Animais , Western Blotting , Cães , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Imunidade Humoral/imunologia , Estudos Longitudinais , Vacinação
12.
Acta Neuropathol ; 118(4): 505-17, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19360426

RESUMO

Beta-amyloid (Abeta) is thought to be a key contributor to the pathogenesis of Alzheimer disease (AD) in the general population and in adults with Down syndrome (DS). Different assembly states of Abeta have been identified that may be neurotoxic. Abeta oligomers can assemble into soluble prefibrillar oligomers, soluble fibrillar oligomers and insoluble fibrils. Using a novel antibody, OC, recognizing fibrils and soluble fibrillar oligomers, we characterized fibrillar Abeta deposits in AD and DS cases. We further compared human specimens to those obtained from the Tg2576 mouse model of AD. Our results show that accumulation of fibrillar immunoreactivity is significantly increased in AD relative to nondemented aged subjects and those with select cognitive impairments (p < 0.0001). Further, there was a significant correlation between the extent of frontal cortex fibrillar deposit accumulation and dementia severity (MMSE r = -0.72). In DS, we observe an early age of onset and age-dependent accumulation of fibrillar OC immunoreactivity with little pathology in similarly aged non-DS individuals. Tg2576 mice show fibrillar accumulation that can be detected as young as 6 months. Interestingly, fibril-specific immunoreactivity was observed in diffuse, thioflavine S-negative Abeta deposits in addition to more mature neuritic plaques. These results suggest that fibrillar deposits are associated with disease in both AD and in adults with DS and their distribution within early Abeta pathology associated with diffuse plaques and correlation with MMSE suggest that these deposits may not be as benign as previously thought.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/metabolismo , Síndrome de Down/metabolismo , Neurofibrilas/metabolismo , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/imunologia , Animais , Anticorpos/metabolismo , Biomarcadores , Córtex Cerebral/patologia , Síndrome de Down/patologia , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Pessoa de Meia-Idade , Neurofibrilas/imunologia , Neurofibrilas/patologia , Neurônios/metabolismo , Neurônios/patologia , Conformação Proteica , Índice de Gravidade de Doença
13.
J Neurosci ; 28(14): 3555-66, 2008 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-18385314

RESUMO

Aged canines (dogs) accumulate human-type beta-amyloid (Abeta) in diffuse plaques in the brain with parallel declines in cognitive function. We hypothesized that reducing Abeta in a therapeutic treatment study of aged dogs with preexisting Abeta pathology and cognitive deficits would lead to cognitive improvements. To test this hypothesis, we immunized aged beagles (8.4-12.4 years) with fibrillar Abeta(1-42) formulated with aluminum salt (Alum) for 2.4 years (25 vaccinations). Cognitive testing during this time revealed no improvement in measures of learning, spatial attention, or spatial memory. After extended treatment (22 vaccinations), we observed maintenance of prefrontal-dependent reversal learning ability. In the brain, levels of soluble and insoluble Abeta(1-40) and Abeta(1-42) and the extent of diffuse plaque accumulation was significantly decreased in several cortical regions, with preferential reductions in the prefrontal cortex, which is associated with a maintenance of cognition. However, the amount of soluble oligomers remained unchanged. The extent of prefrontal Abeta was correlated with frontal function and serum anti-Abeta antibody titers. Thus, reducing total Abeta may be of limited therapeutic benefit to recovery of cognitive decline in a higher mammalian model of human brain aging and disease. Immunizing animals before extensive Abeta deposition and cognitive decline to prevent oligomeric or fibrillar Abeta formation may have a greater impact on cognition and also more directly evaluate the role of Abeta on cognition in canines. Alternatively, clearing preexisting Abeta from the brain in a treatment study may be more efficacious for cognition if combined with a second intervention that restores neuron health.


Assuntos
Envelhecimento , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Cognição/fisiologia , Imunização , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Análise de Variância , Animais , Comportamento Animal/fisiologia , Encéfalo/imunologia , Encéfalo/metabolismo , Comportamento de Escolha/fisiologia , Aprendizagem por Discriminação/fisiologia , Cães , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Esquemas de Imunização , Estudos Longitudinais , Masculino , Memória/fisiologia , Emaranhados Neurofibrilares/patologia , Testes Neuropsicológicos
14.
Mol Neurodegener ; 2: 18, 2007 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-17897471

RESUMO

BACKGROUND: Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD), amyloid accumulates in several distinct types of insoluble plaque deposits, intracellular Abeta and as soluble oligomers and the relationships between these deposits and their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize distinct assembly states of amyloids, including prefibrillar oligomers and fibrils. RESULTS: We immunized rabbits with a morphologically homogeneous population of Abeta42 fibrils. The resulting immune serum (OC) specifically recognizes fibrils, but not random coil monomer or prefibrillar oligomers, indicating fibrils display a distinct conformation dependent epitope that is absent in prefibrillar oligomers. The fibril epitope is also displayed by fibrils of other types of amyloids, indicating that the epitope is a generic feature of the polypeptide backbone. The fibril specific antibody also recognizes 100,000 x G soluble fibrillar oligomers ranging in size from dimer to greater than 250 kDa on western blots. The fibrillar oligomers recognized by OC are immunologically distinct from prefibrillar oligomers recognized by A11, even though their sizes overlap broadly, indicating that size is not a reliable indicator of oligomer conformation. The immune response to prefibrillar oligomers and fibrils is not sequence specific and antisera of the same specificity are produced in response to immunization with islet amyloid polypeptide prefibrillar oligomer mimics and fibrils. The fibril specific antibodies stain all types of amyloid deposits in human AD brain. Diffuse amyloid deposits stain intensely with anti-fibril antibody although they are thioflavin S negative, suggesting that they are indeed fibrillar in conformation. OC also stains islet amyloid deposits in transgenic mouse models of type II diabetes, demonstrating its generic specificity for amyloid fibrils. CONCLUSION: Since the fibril specific antibodies are conformation dependent, sequence-independent, and recognize epitopes that are distinct from those present in prefibrillar oligomers, they may have broad utility for detecting and characterizing the accumulation of amyloid fibrils and fibrillar type oligomers in degenerative diseases.

15.
J Immunol ; 174(3): 1580-6, 2005 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-15661919

RESUMO

Immunization of amyloid precursor protein transgenic mice with fibrillar beta-amyloid (Abeta) prevents Alzheimer's disease (AD)-like neuropathology. The first immunotherapy clinical trial used fibrillar Abeta, containing the B and T cell self epitopes of Abeta, as the immunogen formulated with QS21 as the adjuvant in the vaccine. Unfortunately, the clinical trial was halted during the phase II stage when 6% of the participants developed meningoencephalitis. The cause of the meningoencephalitis in the patients that received the vaccine has not been definitively determined; however, analysis of two case reports from the AN-1792 vaccine trial suggest that the meningoencephalitis may have been caused by a T cell-mediated autoimmune response, whereas production of anti-Abeta Abs may have been therapeutic to the AD patients. Therefore, to reduce the risk of an adverse T cell-mediated immune response to Abeta immunotherapy we have designed a prototype epitope vaccine that contains the immunodominant B cell epitope of Abeta in tandem with the synthetic universal Th cell pan HLA DR epitope, pan HLA DR-binding peptide (PADRE). Importantly, the PADRE-Abeta(1-15) sequence lacks the T cell epitope of Abeta. Immunization of BALB/c mice with the PADRE-Abeta(1-15) epitope vaccine produced high titers of anti-Abeta Abs. Splenocytes from immunized mice showed robust T cell stimulation in response to peptides containing PADRE. However, splenocytes from immunized mice were not reactivated by the Abeta peptide. New preclinical trials in amyloid precursor protein transgenic mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse events that occurred in the first clinical trial.


Assuntos
Doença de Alzheimer/terapia , Vacinas contra Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Antígenos HLA-DR/metabolismo , Epitopos Imunodominantes/imunologia , Vacinas Antimaláricas/imunologia , Fragmentos de Peptídeos/imunologia , Doença de Alzheimer/imunologia , Vacinas contra Alzheimer/administração & dosagem , Vacinas contra Alzheimer/uso terapêutico , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/uso terapêutico , Animais , Biomarcadores , Epitopos de Linfócito B/administração & dosagem , Epitopos de Linfócito B/uso terapêutico , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/metabolismo , Epitopos de Linfócito T/uso terapêutico , Feminino , Humanos , Epitopos Imunodominantes/administração & dosagem , Epitopos Imunodominantes/uso terapêutico , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina M/biossíntese , Imunoglobulina M/sangue , Subunidade alfa de Receptor de Interleucina-18 , Linfocinas/biossíntese , Vacinas Antimaláricas/metabolismo , Vacinas Antimaláricas/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/uso terapêutico , Ligação Proteica/imunologia , Receptores de Interleucina/biossíntese , Receptores de Interleucina-18 , Baço/citologia , Baço/imunologia , Baço/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
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