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1.
Nutrients ; 13(2)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546262

RESUMO

African Americans have higher incidence of, and mortality from, many health-related problems than European Americans. They also have a 15 to 20-fold higher prevalence of severe vitamin D deficiency. Here we summarize evidence that: (i) this health disparity is partly due to insufficient vitamin D production, caused by melanin in the skin blocking the UVB solar radiation necessary for its synthesis; (ii) the vitamin D insufficiency is exacerbated at high latitudes because of the combination of dark skin color with lower UVB radiation levels; and (iii) the health of individuals with dark skin can be markedly improved by correcting deficiency and achieving an optimal vitamin D status, as could be obtained by supplementation and/or fortification. Moderate-to-strong evidence exists that high 25-hydroxyvitamin D levels and/or vitamin D supplementation reduces risk for many adverse health outcomes including all-cause mortality rate, adverse pregnancy and birth outcomes, cancer, diabetes mellitus, Alzheimer's disease and dementia, multiple sclerosis, acute respiratory tract infections, COVID-19, asthma exacerbations, rickets, and osteomalacia. We suggest that people with low vitamin D status, which would include most people with dark skin living at high latitudes, along with their health care provider, consider taking vitamin D3 supplements to raise serum 25-hydroxyvitamin D levels to 30 ng/mL (75 nmol/L) or possibly higher.


Assuntos
/etiologia , Colecalciferol/administração & dosagem , Suplementos Nutricionais , Disparidades nos Níveis de Saúde , Deficiência de Vitamina D/etnologia , Deficiência de Vitamina D/epidemiologia , Afro-Americanos , Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Antígenos de Neoplasias , Demência/etiologia , Demência/prevenção & controle , Diabetes Mellitus/etiologia , Diabetes Mellitus/prevenção & controle , Feminino , Humanos , Masculino , Prevalência , Estado Asmático/etiologia , Estado Asmático/prevenção & controle , Vitamina D/análogos & derivados , Vitamina D/sangue , Deficiência de Vitamina D/complicações
2.
Neuroimage ; 228: 117728, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33421595

RESUMO

INTRODUCTION: Adults with Down syndrome (DS) are predisposed to Alzheimer's disease (AD) and reveal early amyloid beta (Aß) pathology in the brain. Positron emission tomography (PET) provides an in vivo measure of Aß throughout the AD continuum. Due to the high prevalence of AD in DS, there is need for longitudinal imaging studies of Aß to better characterize the natural history of Aß accumulation, which will aid in the staging of this population for clinical trials aimed at AD treatment and prevention. METHODS: Adults with DS (N = 79; Mean age (SD) = 42.7 (7.28) years) underwent longitudinal [C-11]Pittsburgh compound B (PiB) PET. Global Aß burden was quantified using the amyloid load metric (AßL). Modeled PiB images were generated from the longitudinal AßL data to visualize which regions are most susceptible to Aß accumulation in DS. AßL change was evaluated across Aß(-), Aß-converter, and Aß(+) groups to assess longitudinal Aß trajectories during different stages of AD-pathology progression. AßL change values were used to identify Aß-accumulators within the Aß(-) group prior to reaching the Aß(+) threshold (previously reported as 20 AßL) which would have resulted in an Aß-converter classification. With knowledge of trajectories of Aß(-) accumulators, a new cutoff of Aß(+) was derived to better identify subthreshold Aß accumulation in DS. Estimated sample sizes necessary to detect a 25% reduction in annual Aß change with 80% power (alpha 0.01) were determined for different groups of Aß-status. RESULTS: Modeled PiB images revealed the striatum, parietal cortex and precuneus as the regions with earliest detected Aß accumulation in DS. The Aß(-) group had a mean AßL change of 0.38 (0.58) AßL/year, while the Aß-converter and Aß(+) groups had change of 2.26 (0.66) and 3.16 (1.34) AßL/year, respectively. Within the Aß(-) group, Aß-accumulators showed no significant difference in AßL change values when compared to Aß-converter and Aß(+) groups. An Aß(+) cutoff for subthreshold Aß accumulation was derived as 13.3 AßL. The estimated sample size necessary to detect a 25% reduction in Aß was 79 for Aß(-) accumulators and 59 for the Aß-converter/Aß(+) group in DS. CONCLUSION: Longitudinal AßL changes were capable of distinguishing Aß accumulators from non-accumulators in DS. Longitudinal imaging allowed for identification of subthreshold Aß accumulation in DS during the earliest stages of AD-pathology progression. Detection of active Aß deposition evidenced by subthreshold accumulation with longitudinal imaging can identify DS individuals at risk for AD development at an earlier stage.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Síndrome de Down/complicações , Síndrome de Down/diagnóstico por imagem , Adulto , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Síndrome de Down/patologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Tomografia por Emissão de Pósitrons
3.
Postepy Biochem ; 66(1): 19-22, 2020 03 31.
Artigo em Polonês | MEDLINE | ID: mdl-33320477

RESUMO

Chronic exposure to an unhealthy diet is one of the causes of civilization diseases and significantly affects the average longevity. The impact of diet on health is extremely complicated due to the chemical diversity of its composition. The diet provides over 26,000 biochemicals and even more of their metabolites. Among this diversity, three macronutrients: proteins, carbohydrates and fats can be identified that provide energy, and in addition providing their metabolites. According to the latest concepts of the impact of macronutrients in diet on human health, their mutual proportions and not solely absolute quantities are of great importance. In our article we present a short discussion of our own research on this problem in relation to the incidence of Alzheimer's disease against the background of contemporary biochemical and epidemiological literature.


Assuntos
Doença de Alzheimer/etiologia , Dieta/efeitos adversos , Doença de Alzheimer/epidemiologia , Humanos , Incidência , Fatores de Risco
4.
Environ Health Prev Med ; 25(1): 64, 2020 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-33129280

RESUMO

BACKGROUND: The burden of dementia is growing rapidly and has become a medical and social problem in Japan. Prospective cohort studies have been considered an effective methodology to clarify the risk factors and the etiology of dementia. We aimed to perform a large-scale dementia cohort study to elucidate environmental and genetic risk factors for dementia, as well as their interaction. METHODS: The Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) is a multisite, population-based prospective cohort study of dementia, which was designed to enroll approximately 10,000 community-dwelling residents aged 65 years or older from 8 sites in Japan and to follow them up prospectively for at least 5 years. Baseline exposure data, including lifestyles, medical information, diets, physical activities, blood pressure, cognitive function, blood test, brain magnetic resonance imaging (MRI), and DNA samples, were collected with a pre-specified protocol and standardized measurement methods. The primary outcome was the development of dementia and its subtypes. The diagnosis of dementia was adjudicated by an endpoint adjudication committee using standard criteria and clinical information according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd Revised Edition. For brain MRI, three-dimensional acquisition of T1-weighted images was performed. Individual participant data were pooled for data analyses. RESULTS: The baseline survey was conducted from 2016 to 2018. The follow-up surveys are ongoing. A total of 11,410 individuals aged 65 years or older participated in the study. The mean age was 74.4 years, and 41.9% were male. The prevalence of dementia at baseline was 8.5% in overall participants. However, it was 16.4% among three sites where additional home visit and/or nursing home visit surveys were performed. Approximately two-thirds of dementia cases at baseline were Alzheimer's disease. CONCLUSIONS: The prospective cohort data from the JPSC-AD will provide valuable insights regarding the risk factors and etiology of dementia as well as for the development of predictive models and diagnostic markers for the future onset of dementia. The findings of this study will improve our understanding of dementia and provide helpful information to establish effective preventive strategies for dementia in Japan.


Assuntos
Demência/epidemiologia , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Demência/etiologia , Demência/genética , Meio Ambiente , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco
5.
Science ; 370(6512): 50-56, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004510

RESUMO

Sleep is evolutionarily conserved across all species, and impaired sleep is a common trait of the diseased brain. Sleep quality decreases as we age, and disruption of the regular sleep architecture is a frequent antecedent to the onset of dementia in neurodegenerative diseases. The glymphatic system, which clears the brain of protein waste products, is mostly active during sleep. Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias. The ties that bind sleep, aging, glymphatic clearance, and protein aggregation have shed new light on the pathogenesis of a broad range of neurodegenerative diseases, for which glymphatic failure may constitute a therapeutically targetable final common pathway.


Assuntos
Doença de Alzheimer/etiologia , Sistema Glinfático/fisiopatologia , Transtornos do Sono-Vigília/complicações , Sono , Envelhecimento , Doença de Alzheimer/fisiopatologia , Animais , Aquaporina 4/genética , Doenças Cardiovasculares/etiologia , Humanos , Sistema Linfático/fisiopatologia , Camundongos , Polimorfismo Genético , Proteínas Priônicas/metabolismo , Agregados Proteicos , Transtornos do Sono-Vigília/fisiopatologia
6.
Yakugaku Zasshi ; 140(9): 1129-1139, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32879245

RESUMO

The medical information and communication technology "Kibitan Health Net" was introduced as a part of the medical reconstruction assistance national project in Fukushima. However, its effect on the performance of the pharmacists has not yet been validated in community pharmacy. In this study, we investigated the usefulness of acquisition and utilization of precise medical information from diabetic patients using Kibitan Health Net. The subjects of this study were 18 patients having type 2 diabetes mellitus with a mean HbA1c level of 7.4±1.0 (%). We compared the HbA1c level captured by the pharmacists from the patients (total 72 times) with that updated on Kibitan Health Net (41 times correctly captured by the pharmacists). We next compared the HbA1c levels between the "group that could listen to accurate laboratory data" and the "group that could not listen to accurate laboratory data" using intergroup analysis. After factor analysis between the two groups, we demonstrated that the proportion of patients who could not precisely communicate laboratory results was significantly higher among the elderly population (p<0.05). Recent studies have reported that elderly diabetic patients have a higher risk of cognitive decline and Alzheimer-type dementia resulting in higher brain dysfunction. The utilization of Kibitan Health Net enabled the capturing of precise patient information. These data could make it possible to provide instruction for proper compliance and guidance for recuperation among the elderly diabetic patients, and prevent their cognitive decline due to poor glycemic control, as well as set future therapeutic goals and improve adherence.


Assuntos
Diabetes Mellitus/diagnóstico , Hemoglobina A Glicada/análise , Tecnologia da Informação , Farmacêuticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Doença de Alzheimer/prevenção & controle , Biomarcadores/sangue , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Complicações do Diabetes/etiologia , Complicações do Diabetes/prevenção & controle , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Farmácias , Encaminhamento e Consulta , Adulto Jovem
7.
PLoS One ; 15(9): e0239077, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32960930

RESUMO

The Virtual Supermarket Task (VST) and Sea Hero Quest detect high-genetic-risk Alzheimer`s disease (AD). We aimed to determine their test-retest reliability in a preclinical AD population. Over two time points, separated by an 18-month period, 59 cognitively healthy individuals underwent a neuropsychological and spatial navigation assessment. At baseline, participants were classified as low-genetic-risk of AD or high-genetic-risk of AD. We calculated two-way mixed effects intraclass correlation coefficients (ICC) for task parameters and used repeated measures ANOVAS to determine whether genetic risk or sex contributed to test-retest variability. The egocentric parameter of the VST measure showed the highest test-retest reliability (ICC = .72), followed by the SHQ distance travelled parameter (ICC = .50). Post hoc longitudinal analysis showed that boundary-based navigation predicts worsening episodic memory concerns in high-risk (F = 5.01, P = 0.03), but in not low-risk, AD candidates. The VST and the Sea Hero Quest produced parameters with acceptable test-retest reliability. Further research in larger sample sizes is desirable.


Assuntos
Doença de Alzheimer/diagnóstico , Navegação Espacial , Idoso , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Cognição , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Memória Episódica , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco , Fatores Sexuais
8.
Lancet Neurol ; 19(10): 872-878, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32949547

RESUMO

Studies in experimental animals show transmissibility of amyloidogenic proteins associated with prion diseases, Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. Although these data raise potential concerns for public health, convincing evidence for human iatrogenic transmission only exists for prions and amyloid ß after systemic injections of contaminated growth hormone extracts or dura mater grafts derived from cadavers. Even though these procedures are now obsolete, some reports raise the possibility of iatrogenic transmission of amyloid ß through putatively contaminated neurosurgical equipment. Iatrogenic transmission of amyloid ß might lead to amyloid deposition in the brain parenchyma and blood vessel walls, potentially resulting in cerebral amyloid angiopathy after several decades. Cerebral amyloid angiopathy can cause life-threatening brain haemorrhages; yet, there is no proof that the transmission of amyloid ß can also lead to Alzheimer's dementia. Large, long-term epidemiological studies and sensitive, cost-efficient tools to detect amyloid are needed to better understand any potential routes of amyloid ß transmission and to clarify whether other similar proteopathic seeds, such as tau or α-synuclein, can also be transferred iatrogenically.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Vigilância da População , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , Animais , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Síndrome de Creutzfeldt-Jakob/transmissão , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Fatores de Risco
9.
Hipertens. riesgo vasc ; 37(3): 125-132, jul.-sept. 2020. graf, tab
Artigo em Espanhol | IBECS | ID: ibc-193521

RESUMO

La hipertensión arterial es considerada el principal factor de riesgo vascular modificable que causa daño en forma silente en los vasos del cerebro. Esta injuria vascular cerebral podría ser el núcleo común que justifique los síntomas cognitivos (deterioro cognitivo, demencia y enfermedad de Alzheimer) y conductuales (depresión de inicio tardío) del daño de órgano blanco mediado por la hipertensión arterial. El conocimiento incompleto sobre los complejos vínculos fisiopatológicos que relacionan la hipertensión arterial con los cambios cognitivo-conductuales soslaya la participación del cerebro como órgano blanco subestimando el riesgo cardio y cerebrovascular. La convergencia de deterioro cognitivo, depresión e hipertensión arterial en adultos mayores, advierte sobre la necesidad de una evaluación integral que permita planificar el tratamiento, mejorar pronóstico y contribuir a la disminución del riesgo de demencia y su incidencia


Arterial hypertension is considered the main modifiable vascular risk factor that causes silent damage to brain vessels. This vascular brain injury could be the common nucleus that justifies the cognitive (cognitive impairment, dementia and Alzheimer's disease) and behavioural symptoms (late-life depression) of target organ damage mediated-hypertension. Incomplete knowledge about the complex pathophysiology that links hypertension with cognitive-behavioural changes is overlooking brain involvement and underestimating cardio and cerebrovascular risk. The confluence of cognitive impairment, depression and arterial hypertension in elderly adults, warns of the need for a comprehensive evaluation to plan treatment, improve prognosis and contribute to reducing the risk of dementia and its incidence


Assuntos
Humanos , Hipertensão/fisiopatologia , Hipertensão/psicologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Disfunção Cognitiva/prevenção & controle , Transtornos de Início Tardio/fisiopatologia , Doença de Alzheimer/etiologia , Fatores de Risco
10.
Psychogeriatrics ; 20(5): 726-736, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32767414

RESUMO

AIM: Many researchers argue that Alzheimer's disease is at least partly caused by deposition of amyloid beta (Aß) in the brain. Ferulic acid (FA) and Angelica archangelica (AA) are candidate agents for reducing Aß and improving cognitive function. Feru-guard 100M is a supplement containing FA and AA extract. Using this supplement, we planned to assess the effect of FA and AA on Aß deposition in the human brain. METHODS: This was an open-label, interventional multi-institutional joint study of Kobe University and the Institute of Biomedical Research and Innovation (Kobe, Japan). Seventeen subjects diagnosed with mild cognitive impairment were divided into two groups: the intervention group (n = 10) and the control group (n = 7). The subjects in the intervention group used Feru-guard 100M every day for 48 weeks, whereas the subjects in the control group did not use the supplement. We assessed the differences between the two groups by examining Aß deposition and brain atrophy at 48 weeks and cognitive function every 24 weeks. We used carbon-11-labelled Pittsburgh compound B (PiB) positron emission tomography to evaluate Aß deposition. RESULTS: There were no significant differences in Aß deposition, brain atrophy, and cognitive function between the two groups. Specifically, differences in Aß deposition change in seven regions of interest examined with PiB positron emission tomography, brain atrophy change in four indicators of voxel-based morphometry, and cognitive impairment measured by five psychological tests were not significantly between the two groups. CONCLUSION: Treatment with Feru-guard 100M, a supplement containing FA and AA extract, for 48 weeks did not reduce cortical PiB retention, which reflects Aß deposition. It also did not suppress the aggravation of brain atrophy or decline in cognitive function.


Assuntos
Peptídeos beta-Amiloides/efeitos dos fármacos , Angelica archangelica/química , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico , Ácidos Cumáricos/uso terapêutico , Idoso , Doença de Alzheimer/etiologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina , Atrofia , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Disfunção Cognitiva/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Japão , Masculino , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tiazóis
11.
Nat Commun ; 11(1): 3942, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770063

RESUMO

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.


Assuntos
Doença de Alzheimer/etiologia , Encéfalo/patologia , Fatores de Crescimento Neural/metabolismo , Mapas de Interação de Proteínas , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Conjuntos de Dados como Assunto , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Fatores de Crescimento Neural/genética , Mapeamento de Interação de Proteínas , Proteômica
12.
PLoS One ; 15(7): e0234659, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614834

RESUMO

BACKGROUND: The relationship between poor oral health conditions and cognitive decline is unclear. OBJECTIVE: To examine the association between oral health and cognition in humans and rats. METHODS: In humans: a cross-sectional study was conducted. Cognitive levels were evaluated by the Mini Mental State Examination (MMSE); oral conditions were reflected by the number of missing index teeth, bleeding on probing, and probing pocket depth (PD). In rats: a ligature-induced (Lig) periodontitis model and Aß25-35-induced model of Alzheimer's disease (AD) were established; tumor necrosis factor-α (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), and C-reactive protein levels in the hippocampus and cerebral cortex were detected. RESULTS: MMSE scores for the number of missing index teeth ≥ 7 group were significantly lower than those in the ≤ 6 group. A negative relationship (correlation coefficient ρ = -0.310, P = 0.002) was observed between MMSE scores and number of missing index teeth. More missing index teeth and lower education levels were independent risk factors for cognitive decline. A negative relationship (correlation coefficient ρ = -0.214, P = 0.031) was observed between MMSE scores and average PD. TNF-α and IL-6 levels in the hippocampus of the Lig+AD group were significantly higher than those of the AD group. IL-1 and IL-6 levels in the cerebral cortex of the Lig+AD group were significantly higher than those of the AD group. CONCLUSION: Poor oral health conditions including more missing index teeth and higher average PD may be risk factors for cognitive decline. Periodontitis may increase inflammatory cytokines in rat models of AD.


Assuntos
Transtornos Cognitivos/etiologia , Saúde Bucal , Periodontite/complicações , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Peptídeos beta-Amiloides/toxicidade , Animais , Proteína C-Reativa/análise , Causalidade , Córtex Cerebral/química , China/epidemiologia , Transtornos Cognitivos/epidemiologia , Comorbidade , Estudos Transversais , Índice CPO , Modelos Animais de Doenças , Feminino , Hipocampo/química , Humanos , Interleucina-1/análise , Masculino , Aprendizagem em Labirinto , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fragmentos de Peptídeos/toxicidade , Índice Periodontal , Periodontite/epidemiologia , Periodontite/etiologia , Periodontite/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Fator de Necrose Tumoral alfa/análise
13.
PLoS One ; 15(7): e0235979, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32706773

RESUMO

Alzheimer's disease (AD) is proposed to be induced by abnormal aggregation of amyloidß in the brain. Here, we designed a brain-permeable peptide nanofiber drug from a fragment of heat shock protein to suppress aggregation of the pathogenic proteins. To facilitate delivery of the nanofiber into the brain, a protein transduction domain from Drosophila Antennapedia was incorporated into the peptide sequence. The resulting nanofiber efficiently suppressed the cytotoxicity of amyloid ßby trapping amyloid ß onto its hydrophobic nanofiber surface. Moreover, the intravenously or intranasally injected nanofiber was delivered into the mouse brain, and improved the cognitive function of an Alzheimer transgenic mouse model. These results demonstrate the potential therapeutic utility of nanofibers for the treatment of AD.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/administração & dosagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Transtornos da Memória/prevenção & controle , Nanofibras/administração & dosagem , Placa Amiloide/prevenção & controle , Administração Intranasal , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Encéfalo/efeitos dos fármacos , Feminino , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Camundongos , Camundongos Transgênicos , Nanofibras/química , Placa Amiloide/etiologia , Placa Amiloide/patologia
15.
Neurobiol Aging ; 92: 114-134, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32417748

RESUMO

Evidence suggests that changes in intestinal microbiota may affect the central nervous system. However, it is unclear whether alteration of intestinal microbiota affects progression of Alzheimer's disease (AD). To understand this, wild-type control (C57BL/6) mice were compared with the AppNL-G-F model of disease. We used probiotic supplementation to manipulate the gut microbiota. Fecal samples were collected for microbiota profiling. To study brain and intestinal inflammation, biochemical and histological analyses were performed. Altered metabolic pathways were examined by quantifying eicosanoid and bile acid profiles in the brain and serum using ultraperformance liquid chromatography-tandem mass spectrometry. We observed that brain pathology was associated with intestinal dysbiosis and increased intestinal inflammation and leakiness in AppNL-G-F mice. Probiotic supplementation significantly decreased intestinal inflammation and gut permeability with minimal effect on amyloid-ß, cytokine, or gliosis levels in the brain. Concentrations of several bile acids and prostaglandins were altered in the serum and brain because of AD or probiotic supplementation. Our study characterizes intestinal dysfunction in an AD mouse model and the potential of probiotic intervention to ameliorate this condition.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/microbiologia , Encéfalo/metabolismo , Encéfalo/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Probióticos/administração & dosagem , Probióticos/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Eicosanoides/metabolismo , Feminino , Gliose , Inflamação , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
16.
Sci Rep ; 10(1): 7770, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385326

RESUMO

A burgeoning number of studies are demonstrating aluminium in human brain tissue. While research has both quantified and imaged aluminium in human brain tissue in neurodegenerative and neurodevelopmental disease there are few similar data for brain tissue from non-neurologically impaired donors. We have used microwave assisted acid digestion and transversely heated graphite furnace atomic absorption spectrometry to measure aluminium in twenty brains from donors without recognisable neurodegenerative disease. The aluminium content of 191 tissue samples was invariably low with over 80% of tissues having an aluminium content below 1.0 µg/g dry weight of tissue. The data for these control tissues were compared with data (measured using identical procedures) for sporadic Alzheimer's disease, familial Alzheimer's disease, autism spectrum disorder and multiple sclerosis. Detailed statistical analyses showed that aluminium was significantly increased in each of these disease groups compared to control tissues. We have confirmed previous conclusions that the aluminium content of brain tissue in Alzheimer's disease, autism spectrum disorder and multiple sclerosis is significantly elevated. Further research is required to understand the role played by high levels of aluminium in the aetiology of human neurodegenerative and neurodevelopmental disease.


Assuntos
Alumínio/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Doenças Neurodegenerativas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Alumínio/efeitos adversos , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Transtorno Autístico/etiologia , Transtorno Autístico/metabolismo , Transtorno Autístico/patologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/etiologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Doadores de Tecidos
17.
Adv Exp Med Biol ; 1195: 167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468473

RESUMO

Alzheimer's disease (AD) is the most common type of dementia caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain. In addition to neurodegeneration, AD brains contain high levels of amyloid plaques (APs) and neurofibrillary tangles (NFTs) which are used as neuropathological hallmarks of the disorder. Despite intense research efforts, the mechanism(s) of the AD neurodegeneration are imperfectly understood, hampering efforts for the development of efficient therapeutics. Furthermore, failure of clinical trials to benefit AD patients suggests that AD hallmarks are poor therapeutic targets and supports the suggestion that these hallmarks are sequelae of neurodegeneration. Although genetic evidence seem to support the amyloid theory of AD, additional empirical observations and experimental data are inconsistent with the amyloid/Aß theories of AD [Robakis and Neve (1998), TINS vol. 21 pp.15-19; Robakis (2011) NBA vol. 32, pp 372-379]. This possibility is further supported by data that amyloid plaques and neurofibrillary tangles are found in a number of distinct neurodegenerative disorders and that animal models expressing high levels of AD pathological structures show little neuronal loss. Furthermore, genetic evidence linking genetic loci to disease reveal little about the molecular mechanisms involved. Mutants of APP, PS1, and PS2 cause familial AD (FAD) suggesting these mutants can be used as models to study mechanisms of neurodegeneration. Recent reports show that the ability of efnB1 and BDNF (factors) to rescue neurons from excitotoxicity depends on PS1 but is independent of γ-secretase. Interestingly, PS1 FAD mutations block the ability of factors to protect neurons from toxicity suggesting that FAD mutants may increase neuronal death by blocking neuroprotective activities of brain neurotrophins. Other reports also suggest that proteins involved in FAD have Aß-/γ-secretase-independent functions that can play important roles in AD. Furthermore, non-neuronal brain cells like microglia are implicated in AD pathology.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Ensaios Clínicos como Assunto , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Precursor de Proteína beta-Amiloide , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Humanos , Placa Amiloide , Presenilina-1 , Presenilina-2 , Falha de Tratamento
18.
Sci Rep ; 10(1): 8528, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444841

RESUMO

Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LOAD). Comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. Chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. Coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LOAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease.


Assuntos
Envelhecimento , Doença de Alzheimer/etiologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Menopausa , Estresse Oxidativo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/patologia , Feminino , Humanos , Lipídeos/sangue , Metaboloma , Ratos , Ratos Sprague-Dawley , Biologia de Sistemas , Transcriptoma
19.
Neurobiol Aging ; 92: 75-81, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32408055

RESUMO

The cytokine interleukin 6 (IL-6) has been linked to the pathogenesis of Alzheimer's disease (AD). This is the first study to investigate the genetic and epigenetic interactions in the control of IL-6 in human brain and its relation to AD neuropathology in prefrontal cortex tissues from AD and controls genotyped for the SNP -174 C/G rs1800795, a polymorphic CpG in which the G allele creates a CpG site. Within CC homozygotes there were significantly higher brain levels of IL-6 protein compared to G allele carriers. The C allele that resulted in an absence of methylation at a CpG was also associated with significant changes in methylation at neighboring CpGs. Furthermore, there were significant differences in methylation between CC and CG/GG at CpG sites in the AD and control groups. That DNA methylation was altered in the brains by the presence of rs1800795, which further correlated with protein levels suggests the presence of a polymorphic CpG and genetic-epigenetic interactions in the regulation of IL-6 in the prefrontal cortex within AD brains.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Ilhas de CpG/genética , Ilhas de CpG/fisiologia , Epigênese Genética , Lobo Frontal/metabolismo , Interleucina-6/metabolismo , Polimorfismo de Nucleotídeo Único , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/etiologia , Metilação de DNA , Feminino , Humanos , Masculino
20.
Neurobiol Aging ; 92: 82-91, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32408056

RESUMO

Neuroinflammatory responses mediated by microglia, the resident immune cells of the central nervous system, have long been a subject of study in the field of Alzheimer's disease (AD). Microglia express a wide range of receptors that act as molecular sensors, through which they can fulfill their various functions. In this review, we first analyzed the changes in the expression levels of microglial membrane receptors SR-A, TREM2, CD36, CD33, and CR3 in aging and AD and described the different roles of these receptors in amyloid-beta clearance and inflammatory responses. Two classical hallmarks of AD are extracellular amyloid-beta deposits and intracellular aggregated phosphorylated tau. In AD, microglia reaction was initially thought to be triggered by amyloid deposits. New evidence showed it also associated with increased phosphorylation of tau. However, which first appeared and induced activated microglia is not clear. Then we summarized diverse opinions on it. Besides, as AD is tightly linked to aging, and microglia changes dramatically on aging, yet the relative impacts of both aging and microglia are less frequently considered, so at last, we discussed the roles of aging microglia in AD. We hope to provide a reference for subsequent research.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Encéfalo/citologia , Encéfalo/patologia , Expressão Gênica , Microglia/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Humanos , Inflamação , Antígeno de Macrófago 1/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglia/citologia , Fosforilação , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Proteínas tau/metabolismo
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