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1.
Alzheimers Dement ; 18(10): 1889-1897, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-34978149

RESUMO

INTRODUCTION: The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study (NIA-LOAD FBS) was established to study the genetic etiology of Alzheimer's disease (AD). METHODS: Recruitment focused on families with two living affected siblings and a third first-degree relative similar in age with or without dementia. Uniform assessments were completed, DNA was obtained, as was neuropathology, when possible. Apolipoprotein E (APOE) genotypes, genome-wide single nucleotide polymorphism (SNP) arrays, and sequencing was completed in most families. RESULTS: APOE genotype modified the age-at-onset in many large families. Novel variants and known variants associated with early- and late-onset AD and frontotemporal dementia were identified supporting an international effort to solve AD genetics. DISCUSSION: The NIA-LOAD FBS is the largest collection of familial AD worldwide, and data or samples have been included in 123 publications addressing the genetic etiology of AD. Genetic heterogeneity and variability in the age-at-onset provides opportunities to investigate the complexity of familial AD.


Assuntos
Doença de Alzheimer , National Institute on Aging (U.S.) , Estados Unidos , Humanos , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Idade de Início , Genótipo
2.
Neurobiol Dis ; 148: 105221, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33316368

RESUMO

Alzheimer's disease (AD) has been associated with accumulation of amyloid beta (Aß) peptides in brain, and immunotherapy targeting Aß provides potential for AD prevention. We have used a DNA Aß42 trimer construct for immunization of 3xTg-AD mice and found previously significant reduction of amyloid and tau pathology due to the immunotherapy. We show here that DNA Aß42 immunized 3xTg-AD mice showed better performance in nest building activities and had a higher 24 months survival rate compared to the non-treated AD controls. The analysis of differently expressed genes in brains from 24 months old mice showed significant increases transcript levels between non-immunized AD mice and wild-type controls for genes involved in microglia and astrocyte function, cytokine and inflammatory signaling, apoptosis, the innate and adaptive immune response and are consistent with an inflammatory phenotype in AD. Most of these upregulated genes were downregulated in the DNA Aß42 immunized 3xTg-AD mice due to the vaccine. Transcript numbers for the immediate early genes, Arc, Bdnf, Homer1, Egr1 and cfos, involved in neuronal and neurotransmission pathways which were much lower in the non-immunized 3xTg-AD mice, were restored to wild-type mouse brain levels in DNA Aß42 immunized 3xTg-AD mice indicating positive effects of DNA Aß42 immunotherapy on synapse stability and plasticity. The immune response after immunization is complex, but the multitude of changes after DNA Aß42 immunization shows that this response moves beyond the amyloid hypothesis and into direction of disease prevention.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/imunologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Fragmentos de Peptídeos/imunologia , Transcriptoma/efeitos dos fármacos , Vacinas de DNA/farmacologia , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Imunização , Interferon gama/metabolismo , Interleucina-17/metabolismo , Estimativa de Kaplan-Meier , Longevidade/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Comportamento de Nidação/efeitos dos fármacos , Polímeros , Presenilina-1/genética , Baço/citologia , Baço/metabolismo , Taxa de Sobrevida , Transcriptoma/genética , Proteínas tau/genética
3.
J Neuroinflammation ; 14(1): 149, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28750671

RESUMO

BACKGROUND: We previously found that subjects with amnestic mild cognitive impairment exhibit a pro-inflammatory immune profile in the cerebrospinal fluid similar to multiple sclerosis, a central nervous system autoimmune disease. We therefore hypothesized that early neuroinflammation would reflect increases in brain amyloid burden during amnestic mild cognitive impairment. METHODS: Cerebrospinal fluid and blood samples were collected from 24 participants with amnestic mild cognitive impairment (12 men, 12 women; 66 ± 6 years; 0.5 Clinical Dementia Rating) enrolled in the AETMCI study. Analyses of cerebrospinal fluid and blood included immune profiling by multi-parameter flow cytometry, genotyping for apolipoprotein (APO)ε, and quantification of cytokine and immunoglobin levels. Amyloid (A)ß deposition was determined by 18F-florbetapir positron emission tomography. Spearman rank order correlations were performed to assess simple linear correlation for parameters including amyloid imaging, central and peripheral immune cell populations, and protein cytokine levels. RESULTS: Soluble Aß42 in the cerebrospinal fluid declined as Aß deposition increased overall and in the precuneous and posterior cingulate cortices. Lymphocyte profiling revealed a significant decline in T cell populations in the cerebrospinal fluid, specifically CD4+ T cells, as Aß deposition in the posterior cingulate cortex increased. In contrast, increased Aß burden correlated positively with increased memory B cells in the cerebrospinal fluid, which was exacerbated in APOε4 carriers. For peripheral circulating lymphocytes, only B cell populations decreased with Aß deposition in the precuneous cortex, as peripheral T cell populations did not correlate with changes in brain amyloid burden. CONCLUSIONS: Elevations in brain Aß burden associate with a shift from T cells to memory B cells in the cerebrospinal fluid of subjects with amnestic mild cognitive impairment in this exploratory cohort. These data suggest the presence of cellular adaptive immune responses during Aß accumulation, but further study needs to determine whether lymphocyte populations contribute to, or result from, Aß dysregulation during memory decline on a larger cohort collected at multiple centers. TRIAL REGISTRATION: AETMCI NCT01146717.


Assuntos
Imunidade Adaptativa/fisiologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva , Citocinas/metabolismo , Linfócitos/patologia , Idoso , Compostos de Anilina/metabolismo , Apolipoproteínas E/genética , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/sangue , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/patologia , Etilenoglicóis/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons
4.
Radiology ; 278(1): 198-204, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26218598

RESUMO

PURPOSE: To determine in a large multiethnic cohort the cardiovascular and genetic risk factors associated with smaller volume in the hippocampus, precuneus, and posterior cingulate, and their association with preclinical deficits in cognitive performance in patients younger and older than 50 years. MATERIALS AND METHODS: The institutional review board approved the study and all participants provided written informed consent. Eligible for this study were 1629 participants (700 men and 929 women; mean age, 50.0 years ± 10.2 [standard deviation]) drawn from the population-based Dallas Heart Study who underwent laboratory and clinical analysis in an initial baseline visit and approximately 7 years later underwent brain magnetic resonance imaging with automated volumetry and cognitive assessment with the Montreal Cognitive Assessment (MoCA). Regression analysis showed associations between risk factors and segmental volumes, and associations between these volumes with cognitive performance in participants younger and older than 50 years. RESULTS: Lower hippocampal volume was associated with previous alcohol consumption (standardized estimate, -0.04; P = .039) and smoking (standardized estimate, -0.04; P = .048). Several risk factors correlated with lower total brain, posterior cingulate, and precuneus volumes. Higher total (standardized estimate, 0.06; P = .050), high-density lipoprotein (standardized estimate, 0.07; P = .003), and low-density lipoprotein (standardized estimate, 0.04; P = .037) cholesterol levels were associated with larger posterior cingulate volume, and higher triglyceride levels (standardized estimate, 0.06; P = .004) were associated with larger precuneus volume. Total MoCA score was associated with posterior cingulate volume (standardized estimate, 0.13; P = .001) in younger individuals and with hippocampal (standardized estimate, 0.06; P < .05) and precuneus (standardized estimate, 0.08; P < .023) volumes in older adults. CONCLUSION: Smaller volumes in specific brain regions considered to be early markers of dementia risk were associated with specific cardiovascular disease risk factors and cognitive deficits in a predominantly midlife multiethnic population-based sample. Additionally, the risk factors most associated with these brain volumes differed in participants younger and older than 50 years, as did the association between brain volume and MoCA score.


Assuntos
Encéfalo/patologia , Doenças Cardiovasculares/complicações , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/patologia , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
5.
medRxiv ; 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38196599

RESUMO

BACKGROUND: Few rare variants have been identified in genetic loci from genome wide association studies of Alzheimer's disease (AD), limiting understanding of mechanisms and risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in The NIA Alzheimer's Disease Family Based Study, and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss of function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) of families APOE-e4 was the only variant segregating. However, in 60.3% of families neither APOE-e4 nor missense or LoF variants were found within the GWAS loci. DISCUSSION: Although APOE-ε4 and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.

6.
J Neurol Sci ; 446: 120564, 2023 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-36731358

RESUMO

Alzheimer's disease (AD) is the most common form of dementia found in the elderly and disease progression is associated with accumulation of Amyloid beta 1-42 (Aß42) in brain. An immune-mediated approach as a preventive intervention to reduce amyloid plaques without causing brain inflammation is highly desirable for future clinical use. Genetic immunization, in which the immunizing agent is DNA encoding Aß42, has great potential because the immune response to DNA delivered into the skin is generally non-inflammatory, and thus differs quantitatively and qualitatively from immune responses elicited by peptides, which are inflammatory with production of IFNγ and IL-17 cytokines by activated T cells. DNA immunization has historically been proven difficult to apply to larger mammals. A potential barrier to use DNA immunization in large mammals is the method for delivery of the DNA antigen. We tested jet injection in mice and rabbits and found good antibody production and safe immune responses (no inflammatory cytokines). We found significant reduction of amyloid plaques and Aß peptides in brains of the DNA Aß42 immunized 3xTg-AD mouse model. This study was designed to optimize DNA delivery for possible testing of the DNA Aß42 vaccine for AD prevention in a clinical trial.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos , Coelhos , Animais , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide , Fragmentos de Peptídeos , Imunoterapia , Encéfalo/metabolismo , Citocinas , Imunização/métodos , Injeções a Jato , DNA , Camundongos Transgênicos , Modelos Animais de Doenças , Mamíferos/genética , Mamíferos/metabolismo
7.
Aging Brain ; 3: 100066, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36911262

RESUMO

Background: To investigate how changes in expression of glial genes relate to a progression of Alzheimer's disease (AD) pathology, and how anti-Aß immunotherapy impact these changes, we conducted a transcriptomic analysis for brains from cohorts of 2-, 10-, and 20 month old 3xTg-AD mice, and a cross-sectional study in groups of 20 month-old mice treated with active DNA Aß42 immunization, passive immunotherapy, untreated, and wild-type (wt) controls. Methods: Twenty-four Formalin-Fixed Paraffin-Embedded (FFPE) mouse brain sections were used for the gene expression analyses (nanostring). Adjacent sections from these and additional mouse brains were stained for microglia using antibodies detecting IbaI and Gal3. For a semi-quantitative analysis of increased tau and amyloid pathology with aging and disease progression, a comparison of ELISA results from brains of 12 and 20 months old 3xTg-AD mice were shown. Results: Based on the different comparisons of transcript numbers found the 3xTg-AD age groups with the senescent 20 months old wt control mouse brains, and the 20 months old 3xTg-AD mouse brains with the 20 months old wt control mouse brains, genes were assigned as upregulated due to aging, or due to disease progression, or due to both. The immunohistochemistry of microglia markers revealed that Gal3 might be an important marker for phagocytosing microglia around amyloid plaques. The comparison of the two anti-Aß immunotherapy approaches showed a differential downregulation of inflammatory glial genes. Conclusion: These results are relevant for future clinical trials using active anti-amyloid immunotherapy.

8.
Ann Clin Transl Neurol ; 10(5): 744-756, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36946865

RESUMO

OBJECTIVE: To compute penetrance and recurrence risk using a genome-wide PRS (including and excluding the APOE region) in families with Alzheimer's disease. METHODS: Genotypes from the National Institute on Aging Late-Onset Alzheimer's Disease Family-Based Study and a study of familial Alzheimer's disease in Caribbean Hispanics were used to compute PRS with and without variants in the 2 MB region flanking APOE. PRS was calculated in using clumping/thresholding and Bayesian methods and was assessed for association with Alzheimer's disease and age at onset. Penetrance and recurrence risk for carriers in highest and lowest PRS quintiles were compared separately within APOE-ε4 carriers and non-carriers. RESULTS: PRS excluding the APOE region was strongly associated with clinical and neuropathological diagnosis of AD. PRS association with AD was similar in participants who did not carry an APOE-ε4 allele (OR = 1.74 [1.53-1.91]) compared with APOE-ε4 carriers (1.53 [1.4-1.68]). Compared to the lowest quintile, the highest PRS quintile had a 10% higher penetrance at age 70 (p = 0.0006) and a 20% higher penetrance at age 80 (p < 10e-05). Stratifying by APOE-ε4 allele, PRS in the highest quintile was significantly more penetrant than the lowest quintile, both, within APOE-ε4 carriers (14.5% higher at age 80, p = 0.002) and non-carriers (26% higher at 80, p < 10e-05). Recurrence risk for siblings conferred by a co-sibling in the highest PRS quintile increased from 4% between the ages of 65-74 years to 39% at age 85 and older. INTERPRETATION: PRS can be used to estimate penetrance and recurrence risk in familial Alzheimer's disease among carriers and non-carries of APOE-ε4.


Assuntos
Doença de Alzheimer , Humanos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Penetrância , Teorema de Bayes , Fatores de Risco , Apolipoproteínas E/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-34848502

RESUMO

BACKGROUND AND OBJECTIVES: Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4+ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia. METHODS: Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4+ and CD8+ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort. RESULTS: Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4+ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs. DISCUSSION: Examination of CSF indicates that CD4+ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.


Assuntos
Imunidade Adaptativa/imunologia , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/imunologia , Autoanticorpos/líquido cefalorraquidiano , Linfócitos T CD4-Positivos/metabolismo , Imunidade Inata/imunologia , Idoso , Linfócitos T CD8-Positivos/metabolismo , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome
10.
Cell Mol Neurobiol ; 31(6): 867-74, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21625960

RESUMO

The pathogenesis of Alzheimer's disease (AD) has been strongly associated with the accumulation of amyloid beta (Aß) peptides in brain, and immunotherapy targeting Aß provides potential for AD prevention. A clinical trial in which AD patients were immunized with Aß42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that Aß42 DNA vaccination via gene gun generates a Th2 cellular immune response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell proliferation in response to Aß42 peptide re-stimulation was absent in DNA Aß42 trimer-immunized mice when compared to Aß42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wild-type mice after vaccination with Aß42 trimer DNA and Aß42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1-3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype profiles of the Aß42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce Aß42, but an absent T cell proliferative response and no IFNγ or IL-17 secretion after Aß42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen Aß42 in brain. Therefore, Aß42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/imunologia , DNA/imunologia , Epitopos/imunologia , Imunização , Células Th1/citologia , Células Th17/citologia , Doença de Alzheimer/imunologia , Animais , Proliferação de Células , Citocinas/metabolismo , ELISPOT , Fluoresceínas , Imunidade Humoral , Camundongos , Succinimidas , Células Th1/imunologia , Células Th17/imunologia
11.
Am J Geriatr Psychiatry ; 19(5): 423-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20808139

RESUMO

OBJECTIVES: To test the hypothesis that cardiovascular risk factors (CRFs) influence predisposition to and the clinical course of Alzheimer disease (AD), the authors compared Choctaw Indians, a group with known high CRF with white persons with AD. In addition to CRF history, the authors investigated the frequency of apolipoprotein E4 (apoE4) genotype andplasma homocysteine (HC) levels. METHOD: The authors compared 39 Choctaw Indians with AD and 39 Choctaw Indians without AD to 39 white persons with AD with all groups similar in age. CRF history included diabetes, hypertension, high cholesterol or hypolipidemic agent use, or myocardial infarction. The authors also compared plasma HC concentration and apoE4 allele frequency. RESULTS: Choctaw persons with AD differed significantly from white persons with AD in history of hypertension, diabetes, and in HC values but not from Indians without AD. There was a significantly lower apoE4 allele frequency in Choctaw Indian AD than white persons with AD, and both AD groups had an affected first degree relative significantly more often than Indian controls. There was no relationship between the number of CRF and age at onset among Indians or whites, whereas HC concentration was associated with significantly earlier age of onset for Choctaw Indians but not for whites. CONCLUSIONS: This small study suggests that in Choctaw Indians modifiable risk factors may play more of a role in disease pathogenesis than in whites and that nonmodifiable risk factors such as apoE4 may play less of a role.


Assuntos
Doença de Alzheimer/etnologia , Doença de Alzheimer/epidemiologia , Apolipoproteína E4/genética , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/epidemiologia , Homocisteína/sangue , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteína E4/sangue , Doenças Cardiovasculares/genética , Estudos de Casos e Controles , Diabetes Mellitus/etnologia , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipertensão/etnologia , Indígenas Norte-Americanos/genética , Masculino , Pessoa de Meia-Idade , Oklahoma/epidemiologia , Fatores de Risco , Estatísticas não Paramétricas , População Branca/genética
12.
J Neurol Sci ; 429: 118073, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34517228

RESUMO

We do not have an understanding of the fundamental mechanism of how information is stored and retrieved by the brain. A Universal Brain Code utilized for these functions is proposed here. The basic tenent of the Code is that a memory engram is propagated and guided through the connectome by specific proteins/peptides embedded within the pre-synaptic neuronal membrane corresponding to information provided by afferent electrical currents to the pre-synaptic neuron. It is intended to provide a working approach to this central brain activity and begin the process of investigation based on these ideas which are new and unexplored.


Assuntos
Conectoma , Memória , Encéfalo/diagnóstico por imagem , Humanos , Neurônios
13.
Sci Rep ; 11(1): 14405, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257385

RESUMO

Time-to-fall off an accelerating rotating rod (rotarod) is widely utilized to evaluate rodent motor performance. We reasoned that this simple outcome could be refined with additional measures explicit in the task (however inconspicuously) to examine what we call movement sub-structure. Our goal was to characterize normal variation or motor impairment more robustly than by using time-to-fall. We also hypothesized that measures (or features) early in the sub-structure could anticipate the learning expected of a mouse undergoing serial trials. Using normal untreated and baclofen-treated movement-impaired mice, we defined these features and automated their analysis using paw video-tracking in three consecutive trials, including paw location, speed, acceleration, variance and approximate entropy. Spectral arc length yielded speed and acceleration uniformity. We found that, in normal mice, paw movement smoothness inversely correlated with rotarod time-to-fall for the three trials. Greater approximate entropy in vertical movements, and opposite changes in horizontal movements, correlated with greater first-trial time-to-fall. First-trial horizontal approximate entropy in the first few seconds predicted subsequent time-to-fall. This allowed for the separation, after only one rotarod trial, of different-weight, untreated mouse groups, and for the detection of mice otherwise unimpaired after baclofen, which displayed a time-to-fall similar to control. A machine-learning support vector machine classifier corroborated these findings. In conclusion, time-to-fall off a rotarod correlated well with several measures, including some obtained during the first few seconds of a trial, and some responsive to learning over the first two trials, allowing for predictions or preemptive experimental manipulations before learning completion.


Assuntos
Destreza Motora , Animais , Aprendizagem , Masculino , Camundongos , Movimento , Teste de Desempenho do Rota-Rod
16.
JAMA ; 302(16): 1796-802, 2009 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-19861672

RESUMO

CONTEXT: DNA beta-amyloid(1-42) (Abeta42) trimer immunization was developed to produce specific T helper 2 cell (T(H)2)-type antibodies to provide an effective and safe therapy for Alzheimer disease (AD) by reducing elevated levels of Abeta42 peptide that occur in the brain of patients with AD. OBJECTIVE: To compare the immune response in wild-type mice after immunization with DNA Abeta42 trimer and Abeta42 peptide. DESIGN AND INTERVENTION: Wild-type mice received either 4 microg of DNA Abeta42 trimer immunization administered with gene gun (n = 8) or intraperitoneal injection of 100 microg of human Abeta42 peptide with the adjuvant Quil A (n = 8). Titers, epitope mapping, and isotypes of the Abeta42-specific antibodies were analyzed. MAIN OUTCOME MEASURES: Antibody titers, mapping of binding sites (epitopes), isotype profiles of the Abeta42-specific antibodies, and T-cell activation. RESULTS: DNA Abeta42 trimer immunization resulted in antibody titers with a mean of 15 microg per milliliter of plasma. The isotype profile of the antibodies differed markedly. A predominant IgG1 antibody response was found in the DNA-immunized mice, indicating a T(H)2 type of immune response (IgG1/IgG2a ratio of 10). The peptide-immunized mice showed a mixed T(H)1/T(H)2 immune response (IgG1/IgG2a ratio of 1) (P < .001). No increased T-cell proliferation was observed in the DNA-immunized mice (P = .03). CONCLUSION: In this preliminary study in a wild-type mouse model, DNA Abeta42 trimer immunization protocol produced a T(H)2 immune response and appeared to have low potential to cause an inflammatory T-cell response.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/genética , Imunoterapia Ativa , Fragmentos de Peptídeos/genética , Vacinas de DNA/uso terapêutico , Adjuvantes Imunológicos , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Animais , Formação de Anticorpos , Citocinas/biossíntese , Modelos Animais de Doenças , Mapeamento de Epitopos , Feminino , Humanos , Imunoglobulina G/imunologia , Camundongos , Fragmentos de Peptídeos/imunologia , Células Th1/imunologia , Células Th2/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia
17.
Arch Neurol ; 65(3): 329-34, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18332245

RESUMO

The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Genoma , Idade de Início , Precursor de Proteína beta-Amiloide/genética , Apolipoproteína E4/genética , Humanos , Presenilina-1/genética , Presenilina-2/genética
18.
J Neurol Sci ; 264(1-2): 1-8, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17707411

RESUMO

Stanley Prusiner was the first to promote the concept of misfolded proteins as a cause for neurological disease. It has since been shown by him and other investigators that the scrapie isoform of prion protein (PrP(Sc)) functions as an infectious agent in numerous human and non-human disorders of the central nervous system (CNS). Interestingly, other organ systems appear to be less affected, and do not appear to lead to major co-morbidities. The physiological function of the endogenous cellular form of the prion protein (PrP(C)) is much less clear. It is intriguing that PrP(c) is expressed on most tissues in mammals, suggesting not only biological functions outside the CNS, but also a role other than the propagation of its misfolded isotype. In this review, we summarize accumulating in vitro and in vivo evidence regarding the physiological functions of PrP(C) in the nervous system, as well as in lymphoid organs.


Assuntos
Sistema Nervoso Central/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo , Animais , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/fisiopatologia , Sistema Nervoso Central/fisiopatologia , Humanos , Sistema Imunitário/metabolismo , Sistema Imunitário/fisiopatologia , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Proteínas PrPC/metabolismo , Proteínas PrPSc/metabolismo , Doenças Priônicas/fisiopatologia
19.
Alzheimer Dis Assoc Disord ; 22(3): 245-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18580594

RESUMO

Factors predisposing to and associated with atherosclerosis may impact the onset and progression of Alzheimer disease (AD). The high prevalence of atherosclerosis and associated risk factors in American Indians makes them ideal subjects to test this association. We compared frequency of history of hypertension, myocardial infarction, stroke, diabetes, and high cholesterol in 34 American Indians with AD with 34 age-matched American Indian controls, and 34 age-matched whites with probable AD. We also measured waist size, height, and weight, and acquired blood for determination of plasma homocysteine and apolipoprotein E genotype. The 3 groups did not differ significantly in age or sex. History of hypertension and diabetes was significantly more common among American Indian AD patients than Indian controls or whites with AD. The 3 groups did not differ in history of stroke or myocardial infarction. Body mass index was significantly greater in both Indian groups than the white AD group. Plasma homocysteine levels were greater, but not significantly so, in the Indian AD than the Indian control group. Thus, there is preliminary evidence of a modest association between history of hypertension and diabetes and AD in a small sample of American Indians. This suggests that changes in lifestyle factors could influence the expression of AD in American Indians.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/epidemiologia , Aterosclerose/complicações , Aterosclerose/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Aterosclerose/genética , Índice de Massa Corporal , Diabetes Mellitus/epidemiologia , Feminino , Homocisteína/sangue , Humanos , Hipertensão/epidemiologia , Indígenas Norte-Americanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco
20.
Alzheimers Res Ther ; 10(1): 115, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30454039

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most well-known and most common type of age-related dementia. Amyloid deposition and hyperphosphorylation of tau protein are both pathological hallmarks of AD. Using a triple-transgenic mouse model (3xTg-AD) that develops plaques and tangles in the brain similar to human AD, we provide evidence that active full-length DNA amyloid-ß peptide 1-42 (Aß42) trimer immunization leads to reduction of both amyloid and tau aggregation and accumulation. METHODS: Immune responses were monitored by enzyme-linked immunosorbent assay (ELISA) (antibody production) and enzyme-linked immunospot (cellular activation, cytokine production). Brains from 20-month-old 3x Tg-AD mice that had received DNA Aß42 immunotherapy were compared with brains from age- and gender-matched transgenic Aß42 peptide-immunized and control mice by histology, Western blot analysis, and ELISA. Protein kinase activation and kinase levels were studied in Western blots from mouse hemibrain lysates. RESULTS: Quantitative ELISA showed a 40% reduction of Aß42 peptide and a 25-50% reduction of total tau and different phosphorylated tau molecules in the DNA Aß42 trimer-immunized 3xTg-AD mice compared with nonimmunized 3xTg-AD control animals. Plaque and Aß peptide reductions in the brain were due to the anti-Aß antibodies generated following the immunizations. Reductions of tau were likely due to indirect actions such as less Aß in the brain resulting in less tau kinase activation. CONCLUSIONS: The significance of these findings is that DNA Aß42 trimer immunotherapy targets two major pathologies in AD-amyloid plaques and neurofibrillary tangles-in one vaccine without inducing inflammatory T-cell responses, which carry the danger of autoimmune inflammation, as found in a clinical trial using active Aß42 peptide immunization in patients with AD (AN1792).


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Vacinas contra Alzheimer/administração & dosagem , Peptídeos beta-Amiloides/imunologia , Fragmentos de Peptídeos/imunologia , Vacinação/métodos , Proteínas tau/imunologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Transgênicos , Fragmentos de Peptídeos/metabolismo , Proteínas tau/metabolismo
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