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The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer's disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained from AD and people with DS with severe SARS-CoV-2 infections. We examined tau, beta-amyloid (Aß), inflammatory markers and SARS-CoV-2 nucleoprotein in DS, AD, and healthy non-demented controls with COVID-19 and compared with non-infected brain tissue from each disease group (total n = 24). A nested ANOVA was used to determine regional effects of the COVID-19 infection on arborization of astrocytes (Sholl analysis) and percent-stained area of Iba-1 and TMEM 119. SARS-CoV-2 antibodies labeled neurons and glial cells in the frontal cortex of all subjects with COVID-19, and in the hippocampus of two of the three DS COVID-19 cases. SARS-CoV-2-related alterations were observed in peri-vascular astrocytes and microglial cells in the gray matter of the frontal cortex, hippocampus, and para-hippocampal gyrus. Bright field microscopy revealed scattered intracellular and diffuse extracellular Aß deposits in the hippocampus of controls with confirmed SARS-CoV-2 infections. Overall, the present preliminary findings suggest that SARS-CoV-2 infections induce abnormal inflammatory responses in Down syndrome.
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Enfermedad de Alzheimer , Encéfalo , COVID-19 , Síndrome de Down , Humanos , Síndrome de Down/patología , Síndrome de Down/metabolismo , Síndrome de Down/complicaciones , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/virología , Enfermedad de Alzheimer/metabolismo , COVID-19/patología , COVID-19/complicaciones , Masculino , Femenino , Anciano , Persona de Mediana Edad , Encéfalo/patología , Encéfalo/virología , Anciano de 80 o más Años , Astrocitos/patología , Astrocitos/virología , Astrocitos/metabolismo , Péptidos beta-Amiloides/metabolismo , SARS-CoV-2/patogenicidad , Microglía/patología , Microglía/metabolismo , Adulto , Proteínas tau/metabolismoRESUMEN
Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early-onset Alzheimer's disease (AD)-type dementia by early midlife. Despite ongoing clinical trials to treat late-onset AD, individuals with DS are often excluded. Furthermore, timely diagnosis or management is often not available. Of the genetic causes of AD, people with DS represent the largest cohort. Currently, there is a knowledge gap regarding the underlying neurobiological mechanisms of DS-related AD (DS-AD), partly due to limited access to well-characterized brain tissue and biomaterials for research. To address this challenge, we created an international consortium of brain banks focused on collecting and disseminating brain tissue from persons with DS throughout their lifespan, named the Down Syndrome Biobank Consortium (DSBC) consisting of 11 biobanking sites located in Europe, India, and the USA. This perspective describes the DSBC harmonized protocols and tissue dissemination goals.
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Enfermedad de Alzheimer , Síndrome de Down , Humanos , Síndrome de Down/genética , Bancos de Muestras Biológicas , Enfermedad de Alzheimer/genética , Encéfalo , Europa (Continente)RESUMEN
OBJECTIVE: The Alzheimer's continuum is biologically defined by beta-amyloid deposition, which at the earliest stages is superimposed upon white matter degeneration in aging. However, the extent to which these co-occurring changes is characterized is relatively underexplored. The goal of this study was to use diffusional kurtosis imaging (DKI) and biophysical modeling to detect and describe amyloid-related white matter changes in preclinical Alzheimer disease. METHODS: Cognitively unimpaired participants ages 45 to 85 years completed brain magnetic resonance imaging, amyloid positron emission tomography (florbetapir), neuropsychological testing, and other clinical measures at baseline in a cohort study. We tested whether beta-amyloid-negative (AB-) and -positive (AB+) participants differed on DKI-based conventional (ie, fractional anisotropy [FA], mean diffusivity [MD], mean kurtosis) and modeling (ie, axonal water fraction [AWF], extra-axonal radial diffusivity [De,⥠]) metrics, and whether these metrics were associated with other biomarkers. RESULTS: We found significantly greater diffusion restriction (higher FA/AWF, lower MD/De,⥠) in white matter in AB+ than AB- (partial η2 =0.08-0.19), more notably in the extra-axonal space within primarily late myelinating tracts. Diffusion metrics predicted amyloid status incrementally over age (area under the curve = 0.84) with modest yet selective associations, where AWF (a marker of axonal density) correlated with speed/executive functions and neurodegeneration, whereas De,⥠(a marker of gliosis/myelin repair) correlated with amyloid deposition and white matter hyperintensity volume. INTERPRETATION: These results support prior evidence of a nonmonotonic change in diffusion behavior, where an early increase in diffusion restriction is hypothesized to reflect inflammation and myelin repair prior to an ensuing decrease in diffusion restriction, indicating glial and neuronal degeneration. ANN NEUROL 2022;91:864-877.
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Enfermedad de Alzheimer , Sustancia Blanca , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Biomarcadores , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Estudios de Cohortes , Imagen de Difusión por Resonancia Magnética , Imagen de Difusión Tensora/métodos , Humanos , Persona de Mediana Edad , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
Brain pericytes regulate cerebral blood flow, maintain the integrity of the blood-brain barrier (BBB), and facilitate the removal of amyloid ß (Aß), which is critical to healthy brain activity. Pericyte loss has been observed in brains from patients with Alzheimer's disease (AD) and animal models. Our previous data demonstrated that friend leukemia virus integration 1 (Fli-1), an erythroblast transformation-specific (ETS) transcription factor, governs pericyte viability in murine sepsis; however, the role of Fli-1 and its impact on pericyte loss in AD remain unknown. Here, we demonstrated that Fli-1 expression was up-regulated in postmortem brains from a cohort of human AD donors and in 5xFAD mice, which corresponded with a decreased pericyte number, elevated inflammatory mediators, and increased Aß accumulation compared with cognitively normal individuals and wild-type (WT) mice. Antisense oligonucleotide Fli-1 Gapmer administered via intrahippocampal injection decelerated pericyte loss, decreased inflammatory response, ameliorated cognitive deficits, improved BBB dysfunction, and reduced Aß deposition in 5xFAD mice. Fli-1 Gapmer-mediated inhibition of Fli-1 protected against Aß accumulation-induced human brain pericyte apoptosis in vitro. Overall, these studies indicate that Fli-1 contributes to pericyte loss, inflammatory response, Aß deposition, vascular dysfunction, and cognitive decline, and suggest that inhibition of Fli-1 may represent novel therapeutic strategies for AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Proteína Proto-Oncogénica c-fli-1/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Cognición , Disfunción Cognitiva/genética , Disfunción Cognitiva/metabolismo , Humanos , Ratones , Ratones Transgénicos , Pericitos/metabolismoRESUMEN
Inflammation can be resolved by pro-homeostatic lipids called specialized pro-resolving mediators (SPMs) upon activation of their receptors. Dysfunctional inflammatory resolution is now considered as a driver of chronic neuroinflammation and Alzheimer's disease (AD) pathogenesis. We have previously shown that SPM levels were reduced and also that SPM-binding receptors were increased in patients with AD compared to age-matched controls. Individuals with Down syndrome (DS) exhibit accelerated acquisition of AD neuropathology, dementia, and neuroinflammation at an earlier age than the general population. Beneficial effects of inducing resolution in DS have not been investigated previously. The effects of the SPM resolvin E1 (RvE1) in a DS mouse model (Ts65Dn) were investigated with regard to inflammation, neurodegeneration, and memory deficits. A moderate dose of RvE1 for 4 weeks in middle-aged Ts65Dn mice elicited a significant reduction in memory loss, along with reduced levels of serum pro-inflammatory cytokines, and reduced microglial activation in the hippocampus of Ts65Dn mice but had no effects in age-matched normosomic mice. There were no observable adverse side effects in Ts65Dn or in normosomic mice. These findings suggest that SPMs may represent a novel drug target for individuals with DS and others at risk of developing AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Síndrome de Down/tratamiento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/prevención & control , Enfermedad de Alzheimer/patología , Animales , Síndrome de Down/patología , Ácido Eicosapentaenoico/farmacología , Hipocampo/patología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones TransgénicosRESUMEN
The pontine nucleus locus coeruleus (LC) is the primary source of noradrenergic (NE) projections to the brain and is important for working memory, attention, and cognitive flexibility. Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) with high penetrance and often exhibit working memory deficits coupled with degeneration of LC-NE neurons early in the progression of AD pathology. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools that allow targeted manipulation of discrete neuronal populations in the brain without the confounds of off-target effects. We utilized male Ts65Dn mice (a mouse model for DS), and male normosomic (NS) controls to examine the effects of inhibitory DREADDs delivered via an AAV vector under translational control of the synthetic PRSx8, dopamine ß hydroxylase (DßH) promoter. This chemogenetic tool allowed LC inhibition upon administration of the inert DREADD ligand, clozapine-N-oxide (CNO). DREADD-mediated LC inhibition impaired performance in a novel object recognition task and reversal learning in a spatial task. DREADD-mediated LC inhibition gave rise to an elevation of α-adrenoreceptors both in NS and in Ts65Dn mice. Further, microglial markers showed that the inhibitory DREADD stimulation led to increased microglial activation in the hippocampus in Ts65Dn but not in NS mice. These findings strongly suggest that LC signaling is important for intact memory and learning in Ts65Dn mice and disruption of these neurons leads to increased inflammation and dysregulation of adrenergic receptors.
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Neuronas Adrenérgicas/metabolismo , Síndrome de Down/metabolismo , Locus Coeruleus/metabolismo , Trastornos de la Memoria/metabolismo , Neuronas Adrenérgicas/efectos de los fármacos , Animales , Drogas de Diseño , Modelos Animales de Enfermedad , Síndrome de Down/complicaciones , Locus Coeruleus/efectos de los fármacos , Masculino , Ratones , Ratones TransgénicosRESUMEN
BACKGROUND: S-nitrosylation of mitochondrial enzymes involved in energy transfer under nitrosative stress may result in ATP deficiency. We investigated whether α-lipoic acid, a powerful antioxidant, could alleviate nitrosative stress by regulating S-nitrosylation, which could result in retaining the mitochondrial enzyme activity. METHODS: In this study, we have identified the S-nitrosylated forms of subunit 1 of dihydrolipoyllysine succinyltransferase (complex III), and subunit 2 of the α-ketoglutarate dehydrogenase complex by implementing a fluorescence-based differential quantitative proteomics method. RESULTS: We found that the activities of these two mitochondrial enzymes were partially but reversibly inhibited by S-nitrosylation in cultured endothelial cells, and that their activities were partially restored by supplementation of α-lipoic acid. We show that protein S-nitrosylation affects the activity of mitochondrial enzymes that are central to energy supply, and that α-lipoic acid protects mitochondrial enzymes by altering S-nitrosylation levels. CONCLUSIONS: Inhibiting protein S-nitrosylation with α-lipoic acid seems to be a protective mechanism against nitrosative stress. GENERAL SIGNIFICANCE: Identification and characterization of these new protein targets should contribute to expanding the therapeutic power of α-lipoic acid and to a better understanding of the underlying antioxidant mechanisms.
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Complejo III de Transporte de Electrones/metabolismo , Complejo Cetoglutarato Deshidrogenasa/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo , Ácido Tióctico/farmacología , Adenosina Trifosfato/biosíntesis , Animales , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismoRESUMEN
INTRODUCTION: Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) neuropathology and dementia early in life. Blood biomarkers of AD neuropathology would be valuable, as non-AD intellectual disabilities of DS and AD dementia overlap clinically. We hypothesized that elevations of amyloid ß (Aß) peptides and phosphorylated-tau in neuronal exosomes may document preclinical AD. METHODS: AD neuropathogenic proteins Aß1-42, P-T181-tau, and P-S396-tau were quantified by enzyme-linked immunosorbent assays in extracts of neuronal exosomes purified from blood of individuals with DS and age-matched controls. RESULTS: Neuronal exosome levels of Aß1-42, P-T181-tau, and P-S396-tau were significantly elevated in individuals with DS compared with age-matched controls at all ages beginning in childhood. No significant gender differences were observed. DISCUSSION: These early increases in Aß1-42, P-T181-tau, and P-S396-tau in individuals with DS may provide a basis for early intervention as targeted treatments become available.
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Enfermedad de Alzheimer/diagnóstico , Síndrome de Down/sangre , Exosomas/metabolismo , Adolescente , Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Adulto Joven , Proteínas tau/sangreRESUMEN
Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was responsible for the enhanced memory function, the NE prodrug l-threo-dihydroxyphenylserine was administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for treatment in individuals with DS and dementia.
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Antipsicóticos/uso terapéutico , Clozapina/análogos & derivados , Síndrome de Down/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Receptor Muscarínico M3/metabolismo , Animales , Recuento de Células , Clozapina/uso terapéutico , Estudios Cruzados , Drogas de Diseño , Modelos Animales de Enfermedad , Síndrome de Down/genética , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/efectos de la radiación , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/metabolismo , Locus Coeruleus/patología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Mutantes Neurológicos , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Enfermedades Neurodegenerativas/etiología , Receptor Muscarínico M3/genética , Serina/uso terapéuticoRESUMEN
Background: Individuals with Down syndrome (DS) exhibit an almost complete penetrance of Alzheimer's disease (AD) pathology but are underrepresented in clinical trials for AD. The Tau protein is associated with microtubule function in the neuron and is crucial for normal axonal transport. In several different neurodegenerative disorders, Tau misfolding leads to hyper-phosphorylation of Tau (p-Tau), which may seed pathology to bystander cells and spread. This review is focused on current findings regarding p-Tau and its potential to seed pathology as a "prion-like" spreader. It also considers the consequences of p-Tau pathology leading to AD, particularly in individuals with Down syndrome. Methods: Scopus (SC) and PubMed (PM) were searched in English using keywords "tau AND seeding AND brain AND down syndrome". A total of 558 SC or 529 PM potentially relevant articles were identified, of which only six SC or three PM articles mentioned Down syndrome. This review was built upon the literature and the recent findings of our group and others. Results: Misfolded p-Tau isoforms are seeding competent and may be responsible for spreading AD pathology. Conclusions: This review demonstrates recent work focused on understanding the role of neurofibrillary tangles and monomeric/oligomeric Tau in the prion-like spreading of Tau pathology in the human brain.
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Background: Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer's disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD. Objective: The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human tissues. Methods: We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-ß (Aß), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles. Results: Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aß immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases. Conclusions: While inflammation, pTau, and Aß are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology.
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As the world population ages, new molecular targets in aging and Alzheimer's Disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. In this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. We found that rG4 immunostaining strongly increased in prevalence in the hippocampus with both age and with AD severity. We further found that neurofibrillary tangles (NFTs) contained rG4s, that rG4 structure can drive tau aggregation, and that rG4 formation depended on APOE genotype in the human tissue examined. Combined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation drives proteostasis collapse. We propose that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.
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Slowed information processing speed is a defining feature of cognitive aging. Nucleus locus coeruleus (LC) and medial prefrontal regions are targets for understanding slowed processing speed because these brain regions influence neural and behavioral response latencies through their roles in optimizing task performance. Although structural measures of medial prefrontal cortex have been consistently related to processing speed, it is unclear if 1) declines in LC structure underlie this association because of reciprocal connections between LC and medial prefrontal cortex, or 2) if LC declines provide a separate explanation for age-related changes in processing speed. LC and medial prefrontal structural measures were predicted to explain age-dependent individual differences in processing speed in a cross-sectional sample of 43 adults (19-79 years; 63% female). Higher turbo-spin echo LC contrast, based on a persistent homology measure, and greater dorsal cingulate cortical thickness were significantly and each uniquely related to faster processing speed. However, only dorsal cingulate cortical thickness appeared to statistically mediate age-related differences in processing speed. The results suggest that individual differences in cognitive processing speed can be attributed, in part, to structural variation in nucleus LC and medial prefrontal cortex, with the latter key to understanding why older adults exhibit slowed processing speed.
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Locus Coeruleus , Velocidad de Procesamiento , Humanos , Femenino , Anciano , Adulto Joven , Adulto , Persona de Mediana Edad , Masculino , Locus Coeruleus/diagnóstico por imagen , Locus Coeruleus/fisiología , Estudios Transversales , Cognición , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiologíaRESUMEN
Research focused on Down syndrome continued to gain momentum in the last several years and is advancing our understanding of how trisomy 21 (T21) modifies molecular and cellular processes. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. During the COVID pandemic, T21RS held its first virtual conference program, sponsored by the University of California at Irvine, on June 8-10, 2021 and brought together 342 scientists, families, and industry representatives from over 25 countries to share the latest discoveries on underlying cellular and molecular mechanisms of T21, cognitive and behavioral changes, and comorbidities associated with Down syndrome, including Alzheimer's disease and Regression Disorder. Presentations of 91 cutting-edge abstracts reflecting neuroscience, neurology, model systems, psychology, biomarkers, and molecular and pharmacological therapeutic approaches demonstrate the compelling interest and continuing advancement toward innovating biomarkers and therapies aimed at ameliorating health conditions associated with T21.
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Apolipoprotein E (ApoE) is a major lipid carrier protein. In humans, ApoE is expressed in three polymorphic isoforms, which are encoded by three different alleles APOE2, APOE3, and APOE4. In the brains of Alzheimer's disease (AD) patients, each one of these three allelic isoforms is found in several "isoelectric" protein isoforms (qPI), i.e. protein isoforms resulting from PTMs altering the net charge (q) of the polypeptide. AD is a complex disease in which multiple causes and several risk factors affect the onset and disease outcome. A major risk factor for AD is ApoE4; therefore, it is important to characterize the different ApoE qPIs. We have implemented a detergent-based method for isolation and quantitation of protein isoforms, and we found differences in the solubility of protein isoforms depending on the type of solvent used. In this manuscript, we describe these methods and applied them to young human-ApoE targeted replacement mice. Our results indicate that there are no significant differences in the hippocampus proteome of these mice as a function of the APOE genotype.
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Apolipoproteína E3/biosíntesis , Apolipoproteína E4/biosíntesis , Proteoma/análisis , Análisis de Varianza , Animales , Apolipoproteína E3/análisis , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/análisis , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Creatina Quinasa/análisis , Creatina Quinasa/química , Creatina Quinasa/metabolismo , Electroforesis en Gel Bidimensional , Genotipo , Hipocampo/química , Hipocampo/metabolismo , Humanos , Ratones , Ratones Transgénicos , Fosfopiruvato Hidratasa/análisis , Fosfopiruvato Hidratasa/química , Fosfopiruvato Hidratasa/metabolismo , Isoformas de Proteínas , Proteoma/química , Proteoma/genética , Proteoma/metabolismo , Proteómica/métodos , SolubilidadRESUMEN
The accumulation of amyloid beta (Aß) plaques in the brain is a hallmark of Alzheimer's disease (AD) pathology. Microglial activation-mediated neuroinflammation has been implicated in the pathogenesis of AD and the expression levels of interleukin-6 (IL-6) were increased in the brains of AD patients. However, the mechanisms by which IL-6 expression is regulated in human microglia are incompletely understood. Here, we show that Aß1-40 oligomers (Aß40) dose-dependently stimulate IL-6 expression in HMC3 human microglial cells. Treatment with Aß40 promotes the transcription of IL-6 and tumor necrosis factor α (TNFα) mRNAs in both HMC3 and THP-1 cells. Mechanistic studies reveal that Aß40-induced increase of IL-6 secretion is associated with the activation of p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK by BIRB 796 or SB202190 abrogates Aß40-induced increase of IL-6 production. Through analyzing brain specimens, we found that the immunoreactivity for IL-6 and phosphorylated (the activated form) p38 MAPK was markedly higher in microglia of AD patients than in age-matched control subjects. Moreover, our studies identified the co-localization of IL-6 with phosphorylated p38 MAPK in microglia in the cortices of AD patients. Taken together, these results indicate that p38 MAPK is a major regulator of Aß-induced IL-6 production in human microglia, which suggests that targeting p38 MAPK may represent a new approach to ameliorate Aß accumulation-induced neuroinflammation in AD.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Humanos , Interleucina-6/metabolismo , Microglía/metabolismo , Placa Amiloide/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Individuals with Down syndrome (DS) exhibit Alzheimer's disease (AD) pathology at a young age, including amyloid plaques and neurofibrillary tangles (NFTs). Tau pathology can spread via extracellular vesicles, such as exosomes. The cargo of neuron-derived small extracellular vesicles (NDEVs) from individuals with DS contains p-Tau at an early age. The goal of the study was to investigate whether NDEVs isolated from the blood of individuals with DS can spread Tau pathology in the brain of wildtype mice. We purified NDEVs from the plasma of patients with DS-AD and controls and injected small quantities using stereotaxic surgery into the dorsal hippocampus of adult wildtype mice. Seeding competent Tau conformers were amplified in vitro from DS-AD NDEVs but not NDEVs from controls. One month or 4 months post-injection, we examined Tau pathology in mouse brains. We found abundant p-Tau immunostaining in the hippocampus of the mice injected with DS-AD NDEVs compared to injections of age-matched control NDEVs. Double labeling with neuronal and glial markers showed that p-Tau staining was largely found in neurons and, to a lesser extent, in glial cells and that p-Tau immunostaining was spreading along the corpus callosum and the medio-lateral axis of the hippocampus. These studies demonstrate that NDEVs from DS-AD patients exhibit Tau seeding capacity and give rise to tangle-like intracellular inclusions.
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BACKGROUND: Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. METHODS: In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. FINDINGS: We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased ß-amyloid 42 protein production in the mouse brains. INTERPRETATION: This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.
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Péptidos beta-Amiloides/metabolismo , Bacterias/clasificación , Encéfalo/metabolismo , Macrófagos/metabolismo , Fumar Marihuana/psicología , Saliva/microbiología , Animales , Bacterias/genética , Bacterias/aislamiento & purificación , Estudios de Casos y Controles , Línea Celular , ADN Bacteriano/genética , ADN Ribosómico/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Fumar Marihuana/inmunología , Fumar Marihuana/metabolismo , Ratones , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6-9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer's disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and phar-ma-cological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21.
RESUMEN
In order for Alzheimer's disease (AD) to manifest, cells must communicate "pathogenic material" such as proteins, signaling molecules, or genetic material to ensue disease propagation. Small extracellular vesicles are produced via the endocytic pathways and released by nearly all cell types, including neurons. Due to their intrinsic interrelationship with endocytic processes and autophagy, there has been increased interest in studying the role of these neuronally-derived extracellular vesicles (NDEVs) in the propagation of AD. Pathologic cargo associated with AD have been found in a number of studies, and NDEVs have been shown to induce pathogenesis in vivo and in vitro. Exogenous NDEVs are also shown to reduce plaque burden in AD models. Thus, the NDEV has the potential to become a useful biomarker, a pathologic potentiator, and a therapeutic opportunity. While the field of NDEV research in AD is still in its infancy, we review the current literature supporting these three claims.