RESUMEN
Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.
Asunto(s)
Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Transporte Axonal , Animales , Humanos , Ratones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Transporte Axonal/genética , Axones/metabolismo , Axones/patología , Complejo Dinactina/metabolismo , Complejo Dinactina/genética , Dineínas/metabolismo , Endosomas/metabolismo , Endosomas/genética , Lisosomas/metabolismo , Mutación , Variación GenéticaRESUMEN
BACKGROUND: The expression of aquaporin 4 (AQP4) and intermediate filament (IF) proteins is altered in malignant glioblastoma (GBM), yet the expression of the major IF-based cytolinker, plectin (PLEC), and its contribution to GBM migration and invasiveness, are unknown. Here, we assessed the contribution of plectin in affecting the distribution of plasmalemmal AQP4 aggregates, migratory properties, and regulation of cell volume in astrocytes. METHODS: In human GBM, the expression of glial fibrillary acidic protein (GFAP), AQP4 and PLEC transcripts was analyzed using publicly available datasets, and the colocalization of PLEC with AQP4 and with GFAP was determined by immunohistochemistry. We performed experiments on wild-type and plectin-deficient primary and immortalized mouse astrocytes, human astrocytes and permanent cell lines (U-251 MG and T98G) derived from a human malignant GBM. The expression of plectin isoforms in mouse astrocytes was assessed by quantitative real-time PCR. Transfection, immunolabeling and confocal microscopy were used to assess plectin-induced alterations in the distribution of the cytoskeleton, the influence of plectin and its isoforms on the abundance and size of plasmalemmal AQP4 aggregates, and the presence of plectin at the plasma membrane. The release of plectin from cells was measured by ELISA. The migration and dynamics of cell volume regulation of immortalized astrocytes were assessed by the wound-healing assay and calcein labeling, respectively. RESULTS: A positive correlation was found between plectin and AQP4 at the level of gene expression and protein localization in tumorous brain samples. Deficiency of plectin led to a decrease in the abundance and size of plasmalemmal AQP4 aggregates and altered distribution and bundling of the cytoskeleton. Astrocytes predominantly expressed P1c, P1e, and P1g plectin isoforms. The predominant plectin isoform associated with plasmalemmal AQP4 aggregates was P1c, which also affected the mobility of astrocytes most prominently. In the absence of plectin, the collective migration of astrocytes was impaired and the dynamics of cytoplasmic volume changes in peripheral cell regions decreased. Plectin's abundance on the plasma membrane surface and its release from cells were increased in the GBM cell lines. CONCLUSIONS: Plectin affects cellular properties that contribute to the pathology of GBM. The observed increase in both cell surface and released plectin levels represents a potential biomarker and therapeutic target in the diagnostics and treatment of GBMs.
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Glioblastoma , Animales , Humanos , Ratones , Acuaporina 4 , Astrocitos , Biomarcadores , Plectina , Isoformas de ProteínasRESUMEN
The observation that aging is regulated by microRNAs (miRNA) and at the same time represents the greatest risk factor for Alzheimer's disease (AD), prompted us to examine the circulating miRNA network in AD beyond aging. We here show that plasma miRNAs in aging are downregulated and predicted to be preferentially targeted to the extracellular vesicle (EV) content. In AD, miRNAs are further downregulated, display altered proportions of motifs relevant to their loading into EVs and secretion propensity, and are forecast to be found exclusively in EVs. The circulating miRNA network in AD, therefore, reflects pathological exacerbation of the aging process whereby physiological suppression of AD pathology by miRNAs becomes insufficient.
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Enfermedad de Alzheimer , Vesículas Extracelulares , MicroARNs , Humanos , MicroARNs/genética , Enfermedad de Alzheimer/genética , Envejecimiento/genéticaRESUMEN
OBJECTIVE: This study examined associations between physical activity (PA) and neuropsychiatric symptoms (NPS) in older adults free of dementia. METHODS: This cross-sectional study included 3,222 individuals ≥70 years of age (1,655 men; mean±SD age=79.2±5.6; cognitively unimpaired, N=2,723; mild cognitive impairment, N=499) from the population-based Mayo Clinic Study of Aging. PA (taken as a presumed predictor) in midlife (i.e., when participants were 50-65 years of age) and late life (i.e., the year prior to assessment) was assessed with a self-reported, validated questionnaire; PA intensity and frequency were used to calculate composite scores. NPS (taken as presumed outcomes) were assessed with the Neuropsychiatric Inventory Questionnaire, Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). Regression analyses included midlife and late-life PA in each model, which were adjusted for age, sex, education, apolipoprotein E É4 status, and medical comorbidity. RESULTS: Higher late-life PA was associated with lower odds of having apathy (OR=0.89, 95% CI=0.84-0.93), appetite changes (OR=0.92, 95% CI=0.87-0.98), nighttime disturbances (OR=0.95, 95% CI=0.91-0.99), depression (OR=0.94, 95% CI=0.90-0.97), irritability (OR=0.93, 95% CI=0.89-0.97), clinical depression (OR=0.92, 95% CI=0.88-0.97), and clinical anxiety (OR=0.90, 95% CI=0.86-0.94), as well as lower BDI-II (ß estimate=-0.042, 95% CI=-0.051 to -0.033) and BAI (ß estimate=-0.030, 95% CI=-0.040 to -0.021) scores. Higher midlife PA was associated only with higher BDI-II scores (ß estimate=0.011, 95% CI=0.004 to 0.019). Sex modified the associations between PA and NPS. CONCLUSIONS: Late-life PA was associated with a lower likelihood of clinical depression or anxiety and subclinical NPS. These findings need to be confirmed in a cohort study.
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Disfunción Cognitiva , Depresión , Masculino , Humanos , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Depresión/psicología , Estudios Transversales , Pruebas Neuropsicológicas , Envejecimiento , Disfunción Cognitiva/diagnóstico , Ejercicio FísicoRESUMEN
INTRODUCTION: We examined the association between cerebrospinal fluid (CSF)-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms (NPS) in older non-demented adults. METHODS: We included 784 persons (699 cognitively unimpaired, 85 with mild cognitive impairment) aged ≥ 50 years who underwent CSF amyloid beta (Aß42), hyperphosphorylated tau 181 (p-tau), and total tau (t-tau) as well as NPS assessment using Beck Depression and Anxiety Inventories (BDI-II, BAI), and Neuropsychiatric Inventory Questionnaire (NPI-Q). RESULTS: Lower CSF Aß42, and higher t-tau/Aß42 and p-tau/Aß42 ratios were associated with BDI-II and BAI total scores, clinical depression (BDI-II ≥ 13), and clinical anxiety (BAI ≥ 10), as well as NPI-Q-assessed anxiety, apathy, and nighttime behavior. DISCUSSION: CSF Aß42, t-tau/Aß42, and p-tau/Aß42 ratios were associated with NPS in community-dwelling individuals free of dementia. If confirmed by a longitudinal cohort study, the findings have clinical relevance of taking into account the NPS status of individuals with abnormal CSF biomarkers.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Estudios Longitudinales , Proteínas tau/líquido cefalorraquídeo , Envejecimiento , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/patología , Plexo Coroideo/metabolismo , Plexo Coroideo/patología , Proteómica , Envejecimiento , InflamaciónRESUMEN
OBJECTIVE: This study aimed to assess the association of bipolar disorder (BD) with risk of major adverse cardiac events (MACEs) after adjusting for established cardiovascular disease (CVD) risk factors. METHODS: We conducted a population-based historical cohort study using the Rochester Epidemiology Project. Patients older than 30 years with a clinical encounter from 1998 to 2000 with no prior MACE, atrial fibrillation, or heart failure were followed up through March 1, 2016. BD diagnosis was validated by chart review. Cox proportional hazards regression models were adjusted for established CVD risk factors, alcohol use disorder, other substance use disorders (SUDs), and major depressive disorder (MDD). RESULTS: The cohort included 288 individuals with BD (0.81%) and 35,326 individuals without BD as the reference group (Ref). Median (interquartile range) follow-up was 16.5 (14.6-17.5) years. A total of 5636 MACE events occurred (BD, 59; Ref, 5577). Survival analysis showed an association between BD and MACE (median event-free-survival rates: BD, 0.80; Ref, 0.86; log-rank p = .018). Multivariate regression adjusting for age and sex also yielded an association between BD and MACE (hazard ratio [HR] = 1.93; 95% confidence interval [CI] = 1.43-2.52; p < .001). The association remained significant after further adjusting for smoking, diabetes mellitus, hypertension, high-density lipoprotein cholesterol, and body mass index (HR = 1.66; 95% CI = 1.17-2.28; p = .006), and for alcohol use disorder, SUD, and MDD (HR = 1.56; 95% CI = 1.09-2.14; p = .010). CONCLUSIONS: In this study, BD was associated with an increased risk of MACE, which persisted after adjusting for established CVD risk factors, SUDs, and MDD. These results suggest that BD is an independent risk factor for major clinical cardiac disease outcomes.
Asunto(s)
Fibrilación Atrial , Trastorno Bipolar , Enfermedades Cardiovasculares , Trastorno Depresivo Mayor , Trastorno Bipolar/epidemiología , Enfermedades Cardiovasculares/complicaciones , Estudios de Cohortes , Trastorno Depresivo Mayor/complicaciones , Trastorno Depresivo Mayor/epidemiología , Humanos , Factores de RiesgoRESUMEN
INTRODUCTION: We investigated the longitudinal relationship between cortical amyloid deposition, anxiety, and depression and the risk of incident mild cognitive impairment (MCI). METHODS: We followed 1440 community-dwelling, cognitively unimpaired individuals aged ≥ 50 years for a median of 5.5 years. Clinical anxiety and depression were assessed using Beck Anxiety and Depression Inventories (BAI, BDI-II). Cortical amyloid beta (Aß) was measured by Pittsburgh compound B positron emission tomography (PiB-PET) and elevated deposition (PiB+) was defined as standardized uptake value ratio ≥ 1.48. We calculated Cox proportional hazards models with age as the time scale, adjusted for sex, education, and medical comorbidity. RESULTS: Cortical Aß deposition (PiB+) independent of anxiety (BAI ≥ 10) or depression (BDI-II ≥ 13) increased the risk of MCI. There was a significant additive interaction between PiB+ and anxiety (joint effect hazard ratio 6.77; 95% confidence interval 3.58-12.79; P = .031) that is, being PiB+ and having anxiety further amplified the risk of MCI. DISCUSSION: Anxiety modified the association between PiB+ and incident MCI.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/metabolismo , Compuestos de Anilina , Ansiedad/epidemiología , Ansiedad/psicología , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Depresión/epidemiología , Depresión/psicología , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones/métodosRESUMEN
OBJECTIVE: The authors conducted a prospective cohort study to examine the risk of incident mild cognitive impairment (MCI) as predicted by baseline neuropsychiatric symptoms (NPS) and brain regional glucose metabolic dysfunction. METHODS: About 1,363 cognitively unimpaired individuals (52.8% males) aged ≥50 years were followed for a median of 4.8 years to the outcome of incident MCI. NPS were assessed using Beck Depression and Anxiety Inventories and Neuropsychiatric Inventory Questionnaire. Glucose hypometabolism was measured by fluorodeoxyglucose positron emission tomography and defined as standardized uptake value ratio ≤ 1.47 in regions typically affected in Alzheimer disease. Cox proportional hazards models were adjusted for age, sex, education, and APOE ε4 status. RESULTS: Participants with regional glucose hypometabolism and depression (Beck Depression Inventory-II ≥13) had a more than threefold increased risk of incident MCI (hazard ratio [95% confidence interval], 3.66 [1.75, 7.65], p <0.001, χ2â¯=â¯11.83, degree of freedom [df]â¯=â¯1) as compared to the reference group (normal regional glucose metabolism and no depression), and the risk was also significantly elevated (7.21 [3.54, 14.7], p <0.001, χ2â¯=â¯29.68, dfâ¯=â¯1) for participants with glucose hypometabolism and anxiety (Beck Anxiety Inventory ≥10). Having glucose hypometabolism and ≥1 NPS (3.74 [2.40, 5.82], p <0.001, χ2â¯=â¯34.13, dfâ¯=â¯1) or ≥2 NPS (3.89 [2.20, 6.86], p <0.001, χ2â¯=â¯21.92, dfâ¯=â¯1) increased the risk of incident MCI by more than three times, and having ≥3 NPS increased the risk by more than four times (4.12 [2.03, 8.37], p <0.001, χ2â¯=â¯15.39, dfâ¯=â¯1). CONCLUSION: Combined presence of NPS with regional glucose hypometabolism is associated with an increased risk of incident MCI, with fluorodeoxyglucose positron emission tomography appearing to be a stronger driving force of cognitive decline than NPS.
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Envejecimiento/metabolismo , Envejecimiento/psicología , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Glucosa/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Femenino , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Estudios ProspectivosRESUMEN
OBJECTIVE: The purpose of this study was to test the hypothesis that subcortical ß-amyloid (Aß) deposition was associated with elevated scores on standardized measures of depressive and anxiety symptoms when compared with cortical (Aß) deposition in persons without dementia. METHODS: The authors performed a cross-sectional study, derived from the population-based Mayo Clinic Study of Aging, comprising participants aged ≥70 years (N=1,022; 55% males; 28% apolipoprotein E [APOE] ε4 carriers; without cognitive impairment, N=842; mild cognitive impairment; N=180). To assess Aß deposition in cortical and subcortical (the amygdala, striatum, and thalamus) regions, participants underwent Pittsburgh Compound B positron emission tomography (PiB-PET) and completed the Beck Depression Inventory-II (BDI-II) and the Beck Anxiety Inventory (BAI). The investigators ran linear regression models to examine the association between PiB-PET standardized uptake value ratios (SUVRs) in the neocortex and subcortical regions and depressive and anxiety symptoms (BDI-II and BAI total scores). Models were adjusted for age, sex, education level, and APOE ε4 carrier status and stratified by cognitive status (without cognitive impairment, mild cognitive impairment). RESULTS: Cortical PiB-PET SUVRs were associated with depressive symptoms (ß=0.57 [SE=0.13], p<0.001) and anxiety symptoms (ß=0.34 [SE=0.13], p=0.011). PiB-PET SUVRs in the amygdala were associated only with depressive symptoms (ß=0.80 [SE=0.26], p=0.002). PiB-PET SUVRs in the striatum and thalamus were associated with depressive symptoms (striatum: ß=0.69 [SE=0.18], p<0.001; thalamus: ß=0.61 [SE=0.24], p=0.011) and anxiety symptoms (striatum: ß=0.56 [SE=0.18], p=0.002; thalamus: ß=0.65 [SE=0.24], p=0.008). In the mild cognitive impairment subsample, Aß deposition, regardless of neuroanatomic location, was associated with depressive symptoms but not anxiety symptoms. CONCLUSIONS: Elevated amyloid deposition in cortical and subcortical brain regions was associated with higher depressive and anxiety symptoms, although these findings did not significantly differ by cortical versus subcortical Aß deposition. This cross-sectional observation needs to be confirmed by a longitudinal study.
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Péptidos beta-Amiloides/metabolismo , Ansiedad/psicología , Encéfalo/metabolismo , Disfunción Cognitiva/metabolismo , Depresión/psicología , Anciano , Anciano de 80 o más Años , Apolipoproteína E4 , Encéfalo/diagnóstico por imagen , Escalas de Valoración Psiquiátrica Breve , Estudios Transversales , Femenino , Humanos , Estudios Longitudinales , Masculino , Tomografía de Emisión de PositronesRESUMEN
OBJECTIVE: Arterial stiffness (ArSt) describes a loss of arterial wall elasticity and is an independent predictor of cardiovascular events. A cardiometabolic-based chronic disease model integrates concepts of adiposity-based chronic disease (ABCD), dysglycemia-based chronic disease (DBCD), and cardiovascular disease. We assessed if ABCD and DBCD models detect more people with high ArSt compared with traditional adiposity and dysglycemia classifiers using the cardio-ankle vascular index (CAVI). METHODS: We evaluated 2070 subjects aged 25 to 64 years from a random population-based sample. Those with type 1 diabetes were excluded. ABCD and DBCD were defined, and ArSt risk was stratified based on the American Association of Clinical Endocrinologists criteria. RESULTS: The highest prevalence of a high CAVI was in stage 2 ABCD (18.5%) and stage 4 DBCD (31.8%), and the lowest prevalence was in stage 0 ABCD (2.2%). In univariate analysis, stage 2 ABCD and all DBCD stages increased the risk of having a high CAVI compared with traditional classifiers. After adjusting for age and gender, only an inverse association between obesity (body mass index ≥30 kg/m2) and CAVI remained significant. Nevertheless, body mass index was responsible for only 0.3% of CAVI variability. CONCLUSION: The ABCD and DBCD models showed better performance than traditional classifiers to detect subjects with ArSt; however, the variables were not independently associated with age and gender, which might be explained by the complexity and multifactoriality of the relationship of CAVI with the ABCD and DBCD models, mediated by insulin resistance.
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Enfermedades Cardiovasculares , Rigidez Vascular , Índice Tobillo Braquial , Índice de Masa Corporal , Enfermedades Cardiovasculares/epidemiología , Enfermedad Crónica , Endocrinólogos , Humanos , Factores de RiesgoRESUMEN
OBJECTIVE: To determine the prevalence rate and associated risk factors for each stage of the Dysglycemia-Based Chronic Disease (DBCD) model, which 4 distinct stages and prompts early prevention to avert Diabetes and cardiometabolic complications. METHODS: Subjects between 25 and 64 years old from a random population-based sample were evaluated in Czechia from 2013 to 2014 using a cross-sectional design. DBCD stages were: stage 1 "insulin resistance" (inferred risk from abdominal obesity or a family history of diabetes); stage 2 "prediabetes"(fasting glucose between 5.6 and 6.9 mmol/L); stage 3 "type 2 diabetes (T2D)" (self-report of T2D or fasting glucose ≥7 mmol/L); and stage 4 "vascular complications" (T2D with cardiovascular disease). RESULTS: A total of 2147 subjects were included (57.8% women) with a median age of 48 years. The prevalence of each DBCD stage were as follows: 54.2% (stage 1); 10.3% (stage 2), 3.7% (stage 3); and 1.2% (stage 4). Stages 2 to 4 were more frequent in men and stage 1 in women (P < .001). Using binary logistic regression analysis adjusting by age/sex, all DBCD stages were strongly associated with abnormal adiposity, hypertension, dyslipidemia, and smoking status. Subjects with lower educational levels and lower income were more likely to present DBCD. CONCLUSION: Using the new DBCD framework and available metrics, 69.4% of the population had DBCD, identifying far more people at risk than a simple prevalence rate for T2D (9.2% in Czechia, 2013-2014). All stages were associated with traditional cardiometabolic risk factors, implicating common pathophysiologic mechanisms and a potential for early preventive care. The social determinants of health were related with all DBCD stages in alarming proportions and will need to be further studied.
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Diabetes Mellitus Tipo 2 , Adulto , Glucemia , Enfermedad Crónica , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Factores de RiesgoRESUMEN
BACKGROUND: The term arterial stiffness (ArSt) describes structural changes in arterial wall related to the loss of elasticity and is known as an independent predictor of cardiovascular diseases (CVD). The evidence relating to ArSt and triglycerides (TG) shows contradictory results. This paper means to survey the association between high TG and ArSt, utilizing the cardio-ankle vascular index (CAVI). METHODS: Subjects aged between 25 and 64 years from a random population-based sample were evaluated between 2013 and 2016. Data from questionnaires, blood pressure, anthropometric measures, and blood samples were collected and analyzed. CAVI was measured using VaSera VS-1500 N devise. Subjects with a history of CVD or chronic renal disease were excluded. RESULTS: One thousand nine hundred thirty-four participants, 44.7% of males, were included. The median age was 48 (Interquartile Range [IQR] 19) years, TG levels were 1.05 (0.793) mmol/L, and CAVI 7.24 (1.43) points. Prevalence of high CAVI was 10.0% (14.5% in males and 6.4% in females; P < 0.001) and prevalence of hypertriglyceridemia was 20.2% (29.2% in males and 13% in females, P < 0.001). The correlation between TG and CAVI was 0.136 (P < 0.001). High CAVI values were more prevalent among participants with metabolic syndrome (MetS), high blood pressure, dysglycemia, abdominal obesity, high LDL-cholesterol (LDL-c), and high total cholesterol. Using binary regression analysis, high TG were associated with high CAVI, even after adjustment for other MetS components, age, gender, smoking status, LDL-c, and statin treatment (ß = 0.474, OR = 1.607, 95% CI = 1.063-2.429, P = 0.024). CONCLUSION: TG levels were correlated with ArSt, measured as CAVI. High TG was associated with high CAVI independent of multiple cardiometabolic risk factors. Awareness of the risks and targeted treatment of hypertriglyceridemia could further benefit in reducing the prevalence of CVD and events.
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Triglicéridos/sangre , Rigidez Vascular/fisiología , Adulto , Aterosclerosis/sangre , Aterosclerosis/fisiopatología , Femenino , Humanos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/fisiopatología , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Análisis de Regresión , Factores de RiesgoRESUMEN
Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically in APP dynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes. SIGNIFICANCE STATEMENT: The tau protein has a relevant role in the transport of cargos throughout neurons. Dysfunction in tau metabolism underlies several neurological disorders leading to dementia. In the adult human brain, two tau isoforms are found in equal amounts, whereas changes in such equilibrium have been associated with neurodegenerative diseases. We investigated the role of tau in human neurons in culture and found that perturbations in the endogenous balance of tau isoforms were sufficient to impair the transport of the Alzheimer's disease-related amyloid precursor protein (APP), although neuronal morphology was normal. Our results provide evidence of a direct relationship between tau isoform imbalance and defects in axonal transport, which induce an abnormal APP metabolism with important implications in neurodegeneration.
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Precursor de Proteína beta-Amiloide/metabolismo , Transporte Axonal/fisiología , Neuronas/metabolismo , Proteínas tau/metabolismo , Animales , Células Cultivadas , Humanos , Ratones , Neuronas/ultraestructura , Isoformas de Proteínas , Tauopatías/metabolismoRESUMEN
BACKGROUND: Little is known about the association of cortical Aß with depression and anxiety among cognitively normal (CN) elderly persons. METHODS: We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB-) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex. RESULTS: Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00-1.06) and BAI (OR = 1.04; 1.01-1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83-2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.77; 0.97-3.22). CONCLUSIONS: As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.
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Envejecimiento/metabolismo , Envejecimiento/patología , Péptidos beta-Amiloides/metabolismo , Ansiedad/diagnóstico , Encéfalo/metabolismo , Cognición/fisiología , Depresión/diagnóstico , Anciano , Anciano de 80 o más Años , Envejecimiento/fisiología , Ansiedad/psicología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Estudios Transversales , Depresión/psicología , Femenino , Fluorodesoxiglucosa F18/metabolismo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tomografía de Emisión de Positrones , Escalas de Valoración PsiquiátricaRESUMEN
The authors conducted a cross-sectional study to investigate the association between anxiety symptoms and cortical thickness, as well as amygdalar volume. A total of 1,505 cognitively normal participants, aged ≥70 years, were recruited from the Mayo Clinic Study of Aging in Olmsted County, Minnesota, on whom Beck Anxiety Inventory and 3T brain MRI data were available. Even though the effect sizes were small in this community-dwelling group of participants, anxiety symptoms were associated with reduced global cortical thickness and reduced thickness within the frontal and temporal cortex. However, after additionally adjusting for comorbid depressive symptoms, only the association between anxiety symptoms and reduced insular thickness remained significant.
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Envejecimiento/patología , Envejecimiento/psicología , Ansiedad/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Anciano , Ansiedad/epidemiología , Apolipoproteína E4/genética , Comorbilidad , Estudios Transversales , Depresión/diagnóstico por imagen , Depresión/epidemiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Minnesota/epidemiología , Tamaño de los Órganos , Escalas de Valoración PsiquiátricaRESUMEN
The authors compared the risk for subjective cognitive impairment (SCI) between carriers of the apolipoprotein E ε4 (APOE ε4) allele (cases) and APOE ε4 noncarriers (controls). SCI was assessed by a validated self-reported questionnaire. The authors used multivariable logistic regression analyses to compute odds ratios and 95% confidence intervals adjusted for age, sex, education, and marital status. Data were available on 114 participants (83 women; 47 APOE ε4 carriers; mean age, 69 years). The risk for SCI was significantly higher among cases than controls, particularly for those 70 years of age and older. These findings should be considered preliminary until confirmed by a prospective cohort study.
Asunto(s)
Envejecimiento/psicología , Apolipoproteínas E/genética , Trastornos del Conocimiento/genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
Intracellular tau aggregates are the neuropathological hallmark of several neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and cases of frontotemporal dementia, but the link between these aggregates and neurodegeneration remains unclear. Neuronal models recapitulating the main features of tau pathology are necessary to investigate the molecular mechanisms of tau malfunction, but current models show little and inconsistent spontaneous tau aggregation. We show that dorsal root ganglion (DRG) neurons in transgenic mice expressing human P301S tau (P301S-htau) develop tau pathology similar to that found in brain and spinal cord and a significant reduction in mechanosensation occurs before detectable fibrillar tau formation. DRG neuronal cultures established from adult P301S-htau mice at different ages retained the pattern of aberrant tau found in vivo. Moreover, htau became progressively hyperphosphorylated over 2 months in vitro beginning with nonsymptomatic neurons, while hyperphosphorylated P301S-htau-positive neurons from 5-month-old mice cultured for 2 months died preferentially. P301S-htau-positive neurons grew aberrant axons, including spheroids, typically found in human tauopathies. Neurons cultured at advanced stages of tau pathology showed a 60% decrease in the fraction of moving mitochondria. SEG28019, a novel O-GlcNAcase inhibitor, reduced steady-state pSer396/pSer404 phosphorylation over 7 weeks in a significant proportion of DRG neurons showing for the first time the possible beneficial effect of prolonged dosing of O-GlcNAcase inhibitor in vitro. Our system is unique in that fibrillar tau forms without external manipulation and provides an important new tool for understanding the mechanisms of tau dysfunction and for screening of compounds for treatment of tauopathies.
Asunto(s)
Células Receptoras Sensoriales/metabolismo , Tauopatías/metabolismo , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Proteínas tau/biosíntesis , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/patología , Tauopatías/tratamiento farmacológico , Tauopatías/genética , Tauopatías/patología , beta-N-Acetilhexosaminidasas/metabolismo , Proteínas tau/genéticaRESUMEN
Despite the extensive knowledge about the effects of chronic stress on cognition, the underlying mechanisms remain unclear. We conducted a cross-sectional moderation analysis on a population-based sample of 596 adults to examine the age- and sex-specific role of emotion regulation (ER) in the relationship between chronic stress and cognitive performance using validated self-report questionnaires. While women showed no direct or moderated relationship between stress and cognition, men displayed a distinct age-related pattern where stress was negatively associated with poorer cognitive performance at older ages, and the onset of this relationship was detected earlier in men with ER problems. These results showed that suppression of emotions and lack of executive control of ER amplify the negative consequences of chronic stress and suggest that there are sex-specific differences in the decline of ability to cope with long-term exposure to stressors.
Asunto(s)
Regulación Emocional , Masculino , Adulto , Humanos , Femenino , Estudios Transversales , Emociones/fisiología , Cognición/fisiología , Encuestas y CuestionariosRESUMEN
AIM: Astrocytes respond to stressors by acquiring a reactive state characterized by changes in their morphology and function. Molecules underlying reactive astrogliosis, however, remain largely unknown. Given that several studies observed increase in the Amyloid Precursor Protein (APP) in reactive astrocytes, we here test whether APP plays a role in reactive astrogliosis. METHODS: We investigated whether APP instigates reactive astroglios by examining in vitro and in vivo the morphology and function of naive and APP-deficient astrocytes in response to APP and well-established stressors. RESULTS: Overexpression of APP in cultured astrocytes led to remodeling of the intermediate filament network, enhancement of cytokine production, and activation of cellular programs centered around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion abrogated remodeling of the intermediate filament network and blunted expression of IFN-stimulated gene products in response to lipopolysaccharide. Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein observed canonically in astrocytes in response to TBI. CONCLUSIONS: The APP thus represents a candidate molecular inducer and regulator of reactive astrogliosis. This finding has implications for understanding pathophysiology of neurodegenerative and other diseases of the nervous system characterized by reactive astrogliosis and opens potential new therapeutic avenues targeting APP and its pathways to modulate reactive astrogliosis.