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1.
Alzheimers Dement ; 20(7): 4411-4422, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38864416

RESUMO

INTRODUCTION: Brain-derived extracellular vesicles (BEVs) in blood allows for minimally-invasive investigations of central nervous system (CNS) -specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols. METHODS: NDD articles investigating BEVs in blood using polymer-based and/or IP-based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV-enrichment and/or post-enrichment were assessed for CNS- and brain-cell-type-specificity, extracellular domains (ECD+), and presence in EV-databases. RESULTS: A total of 82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. A total of 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV-databases. CONCLUSIONS: We identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers. HIGHLIGHTS: Across NDDs, we identified protocols commonly used for EV/BEV enrichment from blood. We identified protocol steps showing variability that require harmonization. We assessed CNS-specificity of proteins used for BEV-enrichment or found in BEV cargo. CNS-specific EV proteins with ECD+ or without were identified. We recommend evaluation of blood-BEV enrichment using these additional ECD+ proteins.


Assuntos
Biomarcadores , Encéfalo , Vesículas Extracelulares , Doenças Neurodegenerativas , Vesículas Extracelulares/metabolismo , Humanos , Doenças Neurodegenerativas/sangue , Biomarcadores/sangue
2.
bioRxiv ; 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37873207

RESUMO

INTRODUCTION: Brain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of CNS-specific markers of age-related neurodegenerative diseases (NDDs). Polymer-based EV- and immunoprecipitation (IP)-based BEV-enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS-specificity of proteins associated with these protocols. METHODS: NDD articles investigating BEVs in blood using polymer-based and/or IP-based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV-enrichment and/or post-enrichment were assessed for CNS- and brain-cell-type- specificity; extracellular domains (ECD+); and presence in EV-databases. RESULTS: 82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV- databases. DISCUSSION: We identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers.

4.
Brain Commun ; 5(2): fcad074, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37056479

RESUMO

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-ß 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-ß 42/amyloid-ß 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.

5.
J Vis Exp ; (186)2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35993755

RESUMO

Extracellular vesicles (EVs) are biological nanoparticles secreted by all cells for cellular communication and waste elimination. They participate in a vast range of functions by acting on and transferring their cargos to other cells in physiological and pathological conditions. Given their presence in biofluids, EVs represent an excellent resource for studying disease processes and can be considered a liquid biopsy for biomarker discovery. An attractive aspect of EV analysis is that they can be selected based on markers of their cell of origin, thus reflecting the environment of a specific tissue in their cargo. However, one of the major handicaps related to EV isolation methods is the lack of methodological consensuses and standardized protocols. Astrocytes are glial cells with essential roles in the brain. In neurodegenerative diseases, astrocyte reactivity may lead to altered EV cargo and aberrant cellular communication, facilitating/enhancing disease progression. Thus, analysis of astrocyte EVs may lead to the discovery of biomarkers and potential disease targets. This protocol describes a 2-step method of enrichment of astrocyte-derived EVs (ADEVs) from human plasma. First, EVs are enriched from defibrinated plasma via polymer-based precipitation. This is followed by enrichment of ADEVs through ACSA-1-based immunocapture with magnetic micro-beads, where resuspended EVs are loaded onto a column placed in a magnetic field. Magnetically labeled ACSA-1+ EVs are retained within the column, while other EVs flow through. Once the column is removed from the magnet, ADEVs are eluted and are ready for storage and analysis. To validate the enrichment of astrocyte markers, glial fibrillary acidic protein (GFAP), or other specific astrocytic markers of intracellular origin, can be measured in the eluate and compared with the flow-through. This protocol proposes an easy, time-efficient method to enrich ADEVs from plasma that can be used as a platform to examine astrocyte-relevant markers.


Assuntos
Astrócitos , Vesículas Extracelulares , Astrócitos/metabolismo , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Plasma/metabolismo
6.
Int Rev Neurobiol ; 164: 179-233, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36038204

RESUMO

The dementia landscape has undergone a striking paradigm shift. The advances in understanding of neurodegeneration and proteinopathies has changed our approach to patients with cognitive impairment. Firstly, it has recently been shown that the various proteinopathies that are the cause of the dementia begin to build up long before the appearance of any obvious symptoms. This has cemented the idea that there is an urgency in diagnosis as it occurs very late in the pathophysiology of these diseases. Secondly, that accurate diagnosis is required to deliver targeted therapies, that is precision medicine. With this latter point, the realization that various factors of a person need to be considered as they may impact the presentation and progression of disease has risen to the forefront. Two of these factors aside from race and age are biological sex and gender (social construct), as both can have tremendous impact on manifestation of disease. This chapter will cover what is known and remains to be known on the interaction of sex and gender with some of the major causes of dementia.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Demência , Demência/diagnóstico , Demência/epidemiologia , Demência/etiologia , Feminino , Humanos , Masculino , Fatores Sexuais
7.
Adv Exp Med Biol ; 1331: 31-48, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453291

RESUMO

Recent research has demonstrated that degeneration of the basal forebrain cholinergic system, far from being a mere downstream mediator of Alzheimer's disease (AD) symptoms, may play a disease-aggravating role in the continuum of AD pathology. The search for novel biomarkers of the cholinergic deficit in AD and novel therapeutic targets for the sustenance of the basal forebrain cholinergic system has therefore taken on more urgency. A novel model that explains the preferential vulnerability of basal forebrain cholinergic neurons in AD as the result of pathological alterations to nerve growth factor (NGF) metabolism offers an integrated investigative platform for the development of such biomarkers and therapeutics. By positing a reciprocal trophic interaction between the basal forebrain and its target tissues, this model can also explain the disease-modifying nature of the cholinergic deficit in AD and can incorporate other key factors in basal forebrain cholinergic degeneration, including NGF receptor changes and retrograde transport deficits in AD. This chapter will focus on the potential of NGF metabolic pathway biomarkers in AD as well as therapeutic targets to correct NGF metabolic deficits, aiding the development of novel pro-cholinergic therapeutics.


Assuntos
Doença de Alzheimer , Preparações Farmacêuticas , Doença de Alzheimer/tratamento farmacológico , Biomarcadores , Humanos , Redes e Vias Metabólicas , Fator de Crescimento Neural/metabolismo
8.
J Neuroinflammation ; 18(1): 147, 2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34218796

RESUMO

BACKGROUND: Brain inflammation has been increasingly associated with early amyloid accumulation in Alzheimer's disease models; however, evidence of its occurrence in humans remains scarce. To elucidate whether amyloid deposition is associated with neuroinflammation and cognitive deficits, we studied brain inflammatory cytokine expression and cognitive decline in non-demented elderly individuals with and without cerebral amyloid-beta deposition. METHODS: Global cognition, episodic, working, and semantic memory, perceptual speed, visuospatial ability, and longitudinal decline (5.7 ± 3.6 years) in each cognitive domain were compared between elderly individuals (66-79 years) with and without cerebral amyloid-beta deposition. The expression of 20 inflammatory cytokines was analyzed in frozen temporal, parietal, and frontal cortices and compared between older individuals with and without amyloid-beta deposition in each brain region. Correlation analyses were performed to analyze associations between amyloid-beta load, cytokine expression, and cognitive decline. RESULTS: Individuals with cortical amyloid-beta deposition displayed deficits and a faster rate of cognitive decline in perceptual speed as compared with those individuals without amyloid-beta. This decline was positively associated with cortical amyloid-beta levels. Elderly individuals with amyloid-beta deposition had higher levels of IL-1ß, IL-6, and eotaxin-3 in the temporal cortex accompanied by an increase in MCP-1 and IL-1ß in the parietal cortex and a trend towards higher levels of IL-1ß and MCP-1 in the frontal cortex as compared with age-matched amyloid-free individuals. Brain IL-1ß levels displayed a positive association with cortical amyloid burden in each brain region. Finally, differential cytokine expression in each cortical region was associated with cognitive decline. CONCLUSIONS: Elderly individuals with amyloid-beta neuropathology but no symptomatic manifestation of dementia, exhibit cognitive decline and increased brain cytokine expression. Such observations suggest that increased cytokine expression might be an early event in the Alzheimer's continuum.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Idoso , Peptídeos beta-Amiloides/análise , Encéfalo/patologia , Disfunção Cognitiva/patologia , Citocinas/análise , Feminino , Humanos , Mediadores da Inflamação/análise , Estudos Longitudinais , Masculino
9.
Alzheimers Res Ther ; 13(1): 119, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183050

RESUMO

BACKGROUND: There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. METHODS: We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aß42:40 ratio, CSF Aß1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. RESULTS: In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aß42:40 (adj.p = .0001), p-tau (adj.p < .0001), and NFL (adj.p < .0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p = .02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p < .0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p < .002). CONCLUSION: These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Síndrome de Down , Proteína 2 Associada à Membrana da Vesícula/líquido cefalorraquidiano , Adulto , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides , Biomarcadores , Disfunção Cognitiva/líquido cefalorraquidiano , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Síndrome de Down/líquido cefalorraquidiano , Síndrome de Down/complicações , Humanos , Fragmentos de Peptídeos , Proteínas tau
10.
Mol Psychiatry ; 26(10): 6023-6037, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-32488129

RESUMO

The NGF metabolic pathway entails the proteins that mature pro-nerve growth factor (proNGF) to NGF and those that degrade NGF. Basal forebrain cholinergic neurons require NGF for maintenance of cholinergic phenotype, are critical for cognition, and degenerate early in Alzheimer's disease (AD). In AD, NGF metabolism is altered, but it is not known whether this is an early phenomenon, nor how it relates to AD pathology and symptomology. We acquired dorsolateral/medial prefrontal cortex samples from individuals with Alzheimer's dementia, Mild Cognitive Impairment (MCI), or no cognitive impairment with high (HA-NCI) and low (LA-NCI) brain Aß from the Religious Orders Study. Cortical proNGF protein, but not mRNA, was higher in AD, MCI, and HA-NCI, while mature NGF was lower. Plasminogen protein was higher in MCI and AD brain tissue, with plasminogen mRNA not likewise elevated, suggesting diminished activation of the proNGF convertase, plasmin. The plasminogen activator tPA was lower in HA-NCI while neuroserpin, the CNS tPA inhibitor, was higher in AD and MCI cortical samples. Matrix metalloproteinase 9 (MMP9), which degrades NGF, was overactive in MCI and AD. Transcription of the MMP9 inhibitor TIMP1 was lower in HA-NCI. ProNGF levels correlated with plasminogen, neuroserpin, and VAChT while NGF correlated with MMP9 activity. In NCI, proNGF correlated with cerebral Aß and tau deposition and to cognitive performance. In summary, proNGF maturation is impaired in preclinical and clinical AD while mature NGF degradation is enhanced. These differences correlate with cognition, pathology, and cholinergic tone, and may suggest novel biomarkers and therapeutic targets.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/genética , Encéfalo/metabolismo , Humanos , Redes e Vias Metabólicas , Fator de Crescimento Neural/metabolismo
11.
Alzheimers Dement ; 17(4): 605-617, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33226181

RESUMO

BACKGROUND: The discovery that nerve growth factor (NGF) metabolism is altered in Down syndrome (DS) and Alzheimer's disease (AD) brains offered a framework for the identification of novel biomarkers signalling NGF deregulation in AD pathology. METHODS: We examined levels of NGF pathway proteins (proNGF, neuroserpin, tissue plasminogen activator [tPA], and metalloproteases [MMP]) in matched cerebrospinal fluid (CSF)/plasma samples from AD-symptomatic (DSAD) and AD-asymptomatic (aDS) individuals with DS, as well as controls (HC). RESULTS: ProNGF and MMP-3 were elevated while tPA was decreased in plasma from individuals with DS. CSF from individuals with DS showed elevated proNGF, neuroserpin, MMP-3, and MMP-9. ProNGF and MMP-9 in CSF differentiated DSAD from aDS (area under the curve = 0.86, 0.87). NGF pathway markers associated with CSF amyloid beta and tau and differed by sex. DISCUSSION: Brain NGF metabolism changes can be monitored in plasma and CSF, supporting relevance in AD pathology. These markers could assist staging, subtyping, or precision medicine for AD in DS.


Assuntos
Doença de Alzheimer/diagnóstico , Biomarcadores , Síndrome de Down/metabolismo , Síndrome de Down/fisiopatologia , Fator de Crescimento Neural/metabolismo , Adulto , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/fisiopatologia , Síndrome de Down/complicações , Feminino , Humanos , Masculino , Metaloproteinase 3 da Matriz/sangue , Metaloproteinase 3 da Matriz/líquido cefalorraquidiano , Metaloproteinase 9 da Matriz/sangue , Metaloproteinase 9 da Matriz/líquido cefalorraquidiano , Pessoa de Meia-Idade , Neuropeptídeos/sangue , Neuropeptídeos/líquido cefalorraquidiano , Serpinas/sangue , Serpinas/líquido cefalorraquidiano , Transdução de Sinais , Proteínas tau/metabolismo , Neuroserpina
12.
Neurobiol Dis ; 148: 105150, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33130223

RESUMO

Matrix metalloproteinase-3 (MMP-3) has been associated with risk of Alzheimer's disease (AD). In this study we introduce a novel role for MMP-3 in degrading nerve growth factor (NGF) in vivo and examine its mRNA and protein expression across the continuum of AD pathology. We provide evidence that MMP-3 participates in the degradation of mature NGF in vitro and in vivo and that it is secreted from the rat cerebral cortex in an activity-dependent manner. We show that cortical MMP-3 is upregulated in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis. A similar upregulation was found in AD and MCI brains as well as in cognitively normal individuals with elevated amyloid deposition. We also observed that frontal cortex MMP-3 protein levels are higher in males. MMP-3 protein correlated with more AD neuropathology, markers of NGF metabolism, and lower cognitive scores in males but not in females. These results suggest that MMP-3 upregulation in AD might contribute to NGF dysmetabolism, and therefore to cholinergic atrophy and cognitive deficits, in a sex-specific manner. MMP-3 should be further investigated as a biomarker candidate or as a therapeutic target in AD.


Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Metaloproteinase 3 da Matriz/genética , Fator de Crescimento Neural/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Córtex Cerebral/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Proteólise , RNA Mensageiro/metabolismo , Ratos , Ratos Transgênicos , Fatores Sexuais
13.
Brain ; 143(12): 3653-3671, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33206953

RESUMO

Epidemiological and experimental studies suggest that a disease-aggravating neuroinflammatory process is present at preclinical stages of Alzheimer's disease. Given that individuals with Down syndrome are at increased genetic risk of Alzheimer's disease and therefore develop the spectrum of Alzheimer's neuropathology in a uniform manner, they constitute an important population to study the evolution of neuroinflammation across the Alzheimer's continuum. Therefore, in this cross-sectional study, we characterized the brain inflammatory profile across the lifespan of individuals with Down syndrome. Microglial morphology and inflammatory cytokine expression were analysed by immunohistochemistry and electrochemiluminescent-based immunoassays in the frontal cortex from foetuses to adults with Down syndrome and control subjects (16 gestational weeks to 64 years), totalling 127 cases. Cytokine expression in mixed foetal primary cultures and hippocampus of adults with Down syndrome, as well as the effects of sex on cytokine expression were also analysed. A higher microglial soma size-to-process length ratio was observed in the frontal cortex of children and young adults with Down syndrome before the development of full-blown Alzheimer's pathology. Moreover, young adults with Down syndrome also displayed increased numbers of rod-like microglia. Increased levels of interleukin-8 and interleukin-10 were observed in children with Down syndrome (1-10 years; Down syndrome n = 5, controls n = 10) and higher levels of interleukin-1ß, interleukin-1α, interleukin-6, interleukin-8, interleukin-10, interleukin-15, eotaxin-3, interferon gamma-induced protein 10, macrophage-derived chemokine, and macrophage inflammatory protein-beta, were found in young adults with Down syndrome compared to euploid cases (13-25 years, Down syndrome n = 6, controls n = 24). Increased cytokine expression was also found in the conditioned media of mixed cortical primary cultures from second trimester foetuses with Down syndrome (Down syndrome n = 7, controls n = 7). Older adults with Down syndrome (39-68 years, Down syndrome n = 22, controls n = 16) displayed reduced levels of interleukin-10, interleukin-12p40, interferon-gamma and tumour necrosis factor-alpha. Microglia displayed larger somas and shorter processes. Moreover, an increase in dystrophic microglia and rod-like microglia aligning to neurons harbouring tau pathology were also observed. Sex stratification analyses revealed that females with Down syndrome had increased interleukin-6 and interleukin-8 levels compared to males with Down syndrome. Finally, multivariate projection methods identified specific cytokine patterns among individuals with Down syndrome. Our findings indicate the presence of an early and evolving neuroinflammatory phenotype across the lifespan in Down syndrome, a knowledge that is relevant for the discovery of stage-specific targets and for the design of possible anti-inflammatory trials against Alzheimer's disease in this population.


Assuntos
Síndrome de Down/patologia , Encefalite/patologia , Adolescente , Idoso , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Células Cultivadas , Criança , Pré-Escolar , Estudos Transversais , Citocinas/biossíntese , Progressão da Doença , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Lactente , Recém-Nascido , Longevidade , Masculino , Microglia/patologia , Pessoa de Meia-Idade , Gravidez , Tauopatias/patologia , Adulto Jovem
14.
J Alzheimers Dis ; 73(2): 723-739, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31868669

RESUMO

Epidemiological, preclinical, and clinical studies have suggested a role for microdose lithium in reducing Alzheimer's disease (AD) risk by modulating key mechanisms associated with AD pathology. The novel microdose lithium formulation, NP03, has disease-modifying effects in the McGill-R-Thy1-APP transgenic rat model of AD-like amyloidosis at pre-plaque stages, before frank amyloid-ß (Aß) plaque deposition, during which Aß is primarily intraneuronal. Here, we are interested in determining whether the positive effects of microdose lithium extend into early Aß post-plaque stages. We administered NP03 (40µg Li/kg; 1 ml/kg body weight) to McGill-R-Thy1-APP transgenic rats for 12 weeks spanning the transition phase from plaque-free to plaque-bearing. The effect of NP03 on remote working memory was assessed using the novel object recognition task. Levels of human Aß38, Aß40, and Aß42 as well as levels of pro-inflammatory mediators were measured in brain-extracts and plasma using electrochemiluminescent assays. Mature Aß plaques were visualized with a thioflavin-S staining. Vesicular acetylcholine transporter (VAChT) bouton density and levels of chemokine (C-X-C motif) ligand 1 (CXCL1), interleukin-6 (IL-6), and 4-hydroxynonenal (4-HNE) were probed using quantitative immunohistochemistry. During the early Aß post-plaque stage, we find that NP03 rescues functional deficits in object recognition, reduces loss of cholinergic boutons in the hippocampus, reduces levels of soluble and insoluble cortical Aß42 and reduces hippocampal Aß plaque number. In addition, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of Aß plaques.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Citratos/uso terapêutico , Compostos de Lítio/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Placa Amiloide/patologia , Placa Amiloide/prevenção & controle , Aldeídos/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Quimiocinas/metabolismo , Composição de Medicamentos , Encefalite/metabolismo , Encefalite/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Interleucina-6/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Ratos , Ratos Transgênicos , Reconhecimento Psicológico , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
15.
J Am Heart Assoc ; 8(9): e011630, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31057061

RESUMO

Background Arterial stiffness is associated with cognitive decline and dementia; however, the precise mechanisms by which it affects the brain remain unclear. Methods and Results Using a mouse model based on carotid calcification this study characterized mechanisms that could contribute to brain degeneration due to arterial stiffness. At 2 weeks postcalcification, carotid stiffness attenuated resting cerebral blood flow in several brain regions including the perirhinal/entorhinal cortex, hippocampus, and thalamus, determined by autoradiography ( P<0.05). Carotid calcification impaired cerebral autoregulation and diminished cerebral blood flow responses to neuronal activity and to acetylcholine, examined by laser Doppler flowmetry ( P<0.05, P<0.01). Carotid stiffness significantly affected spatial memory at 3 weeks ( P<0.05), but not at 2 weeks, suggesting that cerebrovascular impairments precede cognitive dysfunction. In line with the endothelial deficits, carotid stiffness led to increased blood-brain barrier permeability in the hippocampus ( P<0.01). This region also exhibited reductions in vessel number containing collagen IV ( P<0.01), as did the somatosensory cortex ( P<0.05). No evidence of cerebral microhemorrhages was present. Carotid stiffness did not affect the production of mouse amyloid-ß (Aß) or tau phosphorylation, although it led to a modest increase in the Aß40/Aß42 ratio in frontal cortex ( P<0.01). Conclusions These findings suggest that carotid stiffness alters brain microcirculation and increases blood-brain barrier permeability associated with cognitive impairments. Therefore, arterial stiffness should be considered a relevant target to protect the brain and prevent cognitive dysfunctions.


Assuntos
Comportamento Animal , Encéfalo/irrigação sanguínea , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/complicações , Circulação Cerebrovascular , Cognição , Disfunção Cognitiva/etiologia , Calcificação Vascular/complicações , Rigidez Vascular , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Doenças das Artérias Carótidas/fisiopatologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Masculino , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/metabolismo , Memória Espacial , Fatores de Tempo , Calcificação Vascular/fisiopatologia , Proteínas tau/metabolismo
16.
J Alzheimers Dis ; 67(1): 327-341, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30636741

RESUMO

Biomarker discovery is a major need for earlier dementia diagnosis. We evaluated a plasma signature of amyloid, metallo-proteinases (MMPs), and inflammatory markers in a cohort of at-risk individuals and individuals clinically diagnosed with probable Alzheimer's disease (pAD). Using multiplex arrays, we measured Aß40, Aß42, MMP-1, MMP-3, MMP-9, IFN-γ, TNF-α, IL-6, IL-8, and IL-10 in plasma from 107 individuals followed every 6 months for 3 years. Final diagnoses included: pAD (n = 28), mild cognitive impairment (MCI, n = 30), subjective memory impairment (SMI, n = 30), and asymptomatic (NCI, n = 19). Blood was drawn at final follow-up. We used linear and logistic regressions to examine biomarker associations with prior known decline on the Montreal Cognitive Assessment (MoCA) and the Cambridge Cognitive Examination (CAMCOG); as well disease progression by the time of blood-draw. We derived a biomarker composite from the individual markers, and tested its association with a clinical diagnosis of pAD. Lower Aß40 and Aß42 and higher IL-8, IL-10, and TNF-α were associated with greater cognitive decline per the MoCA and CAMCOG. MMP-3 was higher in SMI, MCI, and pAD than NCI. Whereas the other investigative molecules did not differ between groups, composite scores-created using MoCA/CAMCOG-based trends in Aß40, Aß42, MMP-1, MMP-3, IL-8, IL-10, and TNF-α- were associated with a final diagnosis of pAD (c-statistic 0.732 versus 0.602 for age-sex alone). Thus, plasma amyloid, MMP, and inflammatory biomarkers demonstrated differences in individuals with cognitive deterioration and/or progression to MCI/pAD. Our findings support studying these markers earlier in the continuum of probable AD as well as in specific dementias.


Assuntos
Doença de Alzheimer/sangue , Disfunção Cognitiva/sangue , Demência/sangue , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Disfunção Cognitiva/psicologia , Estudos de Coortes , Demência/psicologia , Diagnóstico Precoce , Feminino , Humanos , Inflamação/sangue , Masculino , Metaloproteases/sangue , Testes Neuropsicológicos , Estudos Retrospectivos , Fatores Sexuais
17.
J Am Heart Assoc ; 8(1): e009372, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30572753

RESUMO

Background Immune cells are key regulators of the vascular inflammatory response characteristic of hypertension. In hypertensive rodents, regulatory T lymphocytes (Treg, CD 4+ CD 25+) prevented vascular injury, cardiac damage, and endothelial dysfunction of mesenteric arteries. Whether Treg modulate the cerebrovascular damage induced by hypertension is unknown. Methods and Results C57 BL /6 mice were perfused with angiotensin II (Ang II ; 1000 ng/kg per minute) for 14 days and adoptive transfer of 3×105 CD 4+ CD 25+ T cells was performed via 2 intravenous injections. Control mice received a sham surgery and PBS . Treg prevented Ang II -induced neurovascular uncoupling ( P<0.05) and endothelial impairment ( P<0.05), evaluated by laser Doppler flowmetry in the somatosensory cortex. The neuroprotective effect of Treg was abolished when they were isolated from mice deficient in interleukin-10. Administration of interleukin-10 (60 ng/d) to hypertensive mice prevented Ang II -induced neurovascular uncoupling ( P<0.05). Treg adoptive transfer also diminished systemic inflammation induced by Ang II ( P<0.05), examined with a peripheral blood cytokine array. Mice receiving Ang II + Treg exhibited reduced numbers of Iba-1+ cells in the brain cortex ( P<0.05) and hippocampus ( P<0.001) compared with mice infused only with Ang II. Treg prevented the increase in cerebral superoxide radicals. Overall, these effects did not appear to be directly modulated by Treg accumulating in the brain parenchyma, because only a nonsignificant number of Treg were detected in brain. Instead, Treg penetrated peripheral tissues such as the kidney, inguinal lymph nodes, and the spleen. Conclusions Treg prevent impaired cerebrovascular responses in Ang II -induced hypertension. The neuroprotective effects of Treg involve the modulation of inflammation in the brain and periphery.


Assuntos
Pressão Sanguínea/fisiologia , Circulação Cerebrovascular/fisiologia , Hipertensão/imunologia , Imunidade Inata , Linfócitos T Reguladores/imunologia , Angiotensina II/toxicidade , Animais , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Camundongos , Camundongos Endogâmicos C57BL
19.
Curr Alzheimer Res ; 15(13): 1220-1230, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30182855

RESUMO

BACKGROUND: Microdose lithium is protective against Alzheimer's disease (AD), although the precise mechanisms through which its protective effects are conferred remain unclear. OBJECTIVE: To further examine the effects during the earliest stages of Aß pathology, we evaluated whether NP03, a microdose lithium formulation, modulates Aß-mediated oxidative damage and neuroinflammation when applied to a rat transgenic model of AD-like amyloidosis overexpressing amyloid precursor protein (APP). METHOD: McGill-R-Thy1-APP transgenic rats and wild-type littermates were treated with NP03 or vehicle formulation for 8 weeks beginning at 3 months of age - a phase preceding Aß plaque deposition in the transgenic rats. RESULTS: Oxidative and nitrosative stress markers, protein-bound 4-hydroxynonenal (HNE) and proteinresident 3-nitrotyrosine (3-NT), inflammatory cytokines production, as well as microglial recruitment towards Aß-burdened neurons were assayed. NP03 significantly decreased cerebral HNE and 3-NT, and reduced production of pro-inflammatory cytokines in McGill-R-Thy1-APP transgenic rats. NP03 further reduced expression of microglia surface receptor Trem2 and led to a corresponding reduction in microglia recruitment towards Aß-burdened neurons in the CA1 region of the hippocampus. CONCLUSION: These results suggest that NP03 may function to slow the AD-like pathology in part by modifying oxidative/nitrosative damage and neuroinflammation, raising the possibility that low doses of microencapsulated lithium might be of therapeutic-preventive value during very early or preclinical AD.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Encefalite/tratamento farmacológico , Encefalite/etiologia , Lítio/uso terapêutico , Placa Amiloide/metabolismo , Aldeídos/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Amiloidose/etiologia , Amiloidose/prevenção & controle , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Camundongos Transgênicos , Mutação/genética , Ratos , Tirosina/análogos & derivados , Tirosina/metabolismo
20.
J Neuroinflammation ; 15(1): 62, 2018 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-29490666

RESUMO

BACKGROUND: Angiotensin II (Ang II), a peptide hormone involved in the development of hypertension, causes systemic and cerebral inflammation, affecting brain regions important for blood pressure control. The cause-and-effect relationship between hypertension and inflammation is two-way, but the role of blood pressure in the induction of cerebral inflammation is less clear. The vulnerability of specific brain regions, particularly those important for memory, is also of interest. METHODS: We used molecular biology approaches, immunohistochemistry, and electron microscopy to examine the interdependence between the hypertensive and pro-inflammatory effects of Ang II. We examined the effect of blood pressure by administering a subpressive (200 ng/kg/min) or a pressive Ang II dose (1000 or 1900 ng/kg/min) with and without hydralazine (150 mg/L) for 1 week and used phenylephrine to increase blood pressure independently of the renin-angiotensin system. RESULTS: Ang II increased ionized calcium-binding adaptor molecule 1 (Iba-1) levels (marker of microgliosis) in the whole brain and in the hippocampus in a dose-dependent manner. Pressive Ang II induced specific changes in microglial morphology, indicating differences in functional phenotype. An increase in hippocampal glial fibrillary acidic protein (GFAP) was seen in mice receiving pressive Ang II, while no induction of cerebral gliosis was observed after 7 days of subpressive Ang II infusion. Although phenylephrine led to increased astrogliosis, it did not affect Iba-1 expression. Pressive Ang II stimulated TNF-α production in the hippocampus, and daily treatment with hydralazine prevented this increase. Hydralazine also reduced GFAP and Iba-1 levels. With longer perfusion (14 days), subpressive Ang II led to some but not all the inflammatory changes detected with the pressive doses, mainly an increase in CD68 and Iba-1 but not of GFAP or TNF-α. CONCLUSIONS: Blood pressure and Ang II differentially contribute to hippocampal inflammation in mice. Control of blood pressure and Ang II levels should prevent or reduce brain inflammation and therefore brain dysfunctions associated with hypertension.


Assuntos
Angiotensina II/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipertensão/induzido quimicamente , Hipertensão/patologia , Animais , Pressão Sanguínea/fisiologia , Hipocampo/metabolismo , Hipertensão/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória
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