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Importance: Preclinical studies suggest that amylin has a U-shaped dose-response association with risk of Alzheimer disease (AD). The association of plasma amylin with AD in humans is unknown. Objectives: To measure amylin concentration in plasma by using enzyme-linked immunosorbent assay and to study the association between plasma amylin, incidence of AD, and brain structure in humans. Design, Setting, and Participants: This cohort study used data from the Framingham Heart Study offspring cohort from 1998 to 2015. Using a Monte Carlo approach, participants were divided into 3 plasma amylin concentration groups: (1) low (<75 pmol/L), (2) high (75-2800 pmol/L), and (3) extremely high (≥2800 pmol/L). Data analyses were conducted October 5, 2017, to December 18, 2018. Exposures: Baseline plasma amylin concentrations at examination 7. Main Outcomes and Measures: Incidence of dementia or AD and brain volumetric measures from structural magnetic resonance imaging data. Results: From the Framingham Heart Study offspring cohort, 3061 participants (mean [SD] age at baseline, 61.0 [9.5] years; 1653 [54.0%] women) who had plasma amylin measurements, dementia incidence, and brain volume measurements on record were included in this study. The distribution of plasma amylin concentrations was highly skewed (median [interquartile range], 7.5 [4.6-18.9] pmol/L; mean [SD], 302.3 [1941.0] pmol/L; range, 0.03-44â¯623.7 pmol/L). Compared with the low plasma amylin concentration group, the high plasma amylin concentration group had a lower rate of AD incidence (2.3% vs 5.6%; P = .04), but the extremely high plasma amylin concentration group had a higher rate of AD incidence (14.3%; P < .001). After adjusting for age, sex, education, body mass index, diabetes, cardiovascular disease, high-density lipoprotein level, and APOE4, high plasma amylin was not associated with decreased AD risk (hazard ratio, 0.42 [95% CI, 0.16-1.14]; P = .09) but was positively associated with volume of gray matter in the temporal lobe (ß = 0.17 [SE, 0.05]; P < .001). In contrast, extremely high plasma amylin concentration was associated with a higher AD risk (hazard ratio, 2.51 [95% CI, 1.38-4.57]; P = .003) but not associated with temporal lobe volume (ß = 0.02 [SE, 0.07]; P = .82). Conclusions and Relevance: This study found that plasma amylin concentration was associated with AD incidence and brain structure with a U-shaped pattern. These findings are consistent with preclinical findings that suggest amylin is a neuropeptide that is physiological; however, at extremely high concentrations, it may lead to amylin aggregation and therefore may be a risk factor for AD.
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Enfermedad de Alzheimer/metabolismo , Apolipoproteína E4/sangre , Encéfalo/patología , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Lipoproteínas HDL/sangre , Anciano , Enfermedad de Alzheimer/epidemiología , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Comorbilidad , Demencia/epidemiología , Femenino , Humanos , Incidencia , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer's disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-ß peptide (Aß)-induced AD pathology in neurons with a dose-dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aß or amylin alone induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aß-induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 µM), amylin lost the effects against the Aß-induced cellular AD pathology and, together with Aß, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 µg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 µg/kg), it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aß and amylin concentrations are elevated, imbalance of Aß and amylin may contribute to brain AD pathogenesis.
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Péptidos beta-Amiloides/toxicidad , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/toxicidad , Sinapsis/efectos de los fármacos , Tauopatías/inducido químicamente , Tauopatías/tratamiento farmacológico , Secuencia de Aminoácidos , Animales , Animales Recién Nacidos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Ratones , Ratones Transgénicos , Neuronas/patología , Embarazo , Ratas , Ratas Wistar , Sinapsis/patología , Tauopatías/patologíaRESUMEN
Glioblastoma multiforme (GBM) is an aggressive primary brain cancer that includes focal amplification of PDGFRα and for which there are no effective therapies. Herein, we report the development of a genetically engineered mouse model of GBM based on autocrine, chronic stimulation of overexpressed PDGFRα, and the analysis of GBM signaling pathways using proteomics. We discover the tubulin-binding protein Stathmin1 (STMN1) as a PDGFRα phospho-regulated target, and that this mis-regulation confers sensitivity to vinblastine (VB) cytotoxicity. Treatment of PDGFRα-positive mouse and a patient-derived xenograft (PDX) GBMs with VB in mice prolongs survival and is dependent on STMN1. Our work reveals a previously unconsidered link between PDGFRα activity and STMN1, and highlight an STMN1-dependent cytotoxic effect of VB in GBM.
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Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Glioblastoma/metabolismo , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Estatmina/metabolismo , Vinblastina/farmacología , Animales , Antineoplásicos/farmacología , Apoptosis , Ciclo Celular , Supervivencia Celular , Células Cultivadas , Biología Computacional , Modelos Animales de Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Trasplante de Neoplasias , Fosforilación , Proteómica , Transducción de SeñalRESUMEN
Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer's disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-ß peptide (Aß), and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (pâ<â0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aß levels, other PCs were associated with both Aß and t-tau levels. A receiver operating characteristic analysis of the PCs was combined with the Aß and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls, and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.
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Enfermedad de Alzheimer/diagnóstico , Disfunción Cognitiva/diagnóstico , Polipéptido Amiloide de los Islotes Pancreáticos/administración & dosificación , Fosfatidilcolinas/sangre , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Biomarcadores/sangre , Disfunción Cognitiva/sangre , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Curva ROC , Proteínas tau/sangreRESUMEN
ROP is a subfamily of small GTP-binding proteins that uniquely exist in plants. It acts as versatile molecular switches that regulate various developmental processes. Some ROP proteins are also reported to affect defense responses, although their exact mechanism is not fully understood. Herein, ROP members in wheat were mined; the functions of three wheat ROP proteins were studied. RT-PCR results showed that the expression of TaRac1 was rapidly and strongly induced after leaf rust infection. TaRac1 interacted with TaCCR in yeast-hybridization assay. The overexpression of TaRac1 in tobacco promoted CCR and CAD gene expression, increased the total lignin content and sinapyl lignin proportion, and then enhanced resistance to tobacco black shank and bacterial wilt diseases. In contrast, TaRac3 and TaRac4 did not show to interact with TaCCR. Furthermore, the overexpression of TaRac3 and TaRac4 did not increase lignin gene expression and lignin accumulation either. Unlike TaRac1, the overexpression of TaRac3 increased susceptibility to both black shank and bacterial wilt pathogens, while overexpression of TaRac4 showed no effect on disease resistance but promoted the root growth in tobacco seedling. These data collectively suggest that TaRac1 in Group II is mainly involved in regulating lignin metabolism which, in turn, responsible for the observed roles in pathogen resistance. TaRac3 and TaRac4 have the minor roles in defense response but may act on regulation in plant developmental processes. These results shed light on the complexity and diverse function of ROP in plant defense pathway.
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Lignina/metabolismo , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Triticum/metabolismo , Regulación de la Expresión Génica de las Plantas , Proteínas de Plantas/genética , Plantas Modificadas Genéticamente/genética , Nicotiana/genética , Nicotiana/metabolismo , Triticum/genéticaRESUMEN
INTRODUCTION: Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimer's disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans. METHODS: We administered a single subcutaneous injection of 60 µg of pramlintide to nondiabetic subjects under fasting conditions. RESULTS: None of the participants developed hypoglycemia after the injection of pramlintide. The pramlintide challenge induced a significant surge of amyloid-ß peptide and a decrease in total tau in the plasma of AD subjects but not in control participants. The pramlintide injection provoked an increase in interleukin 1 receptor antagonist and a decrease in retinol-binding protein 4, which separates AD subjects from control subjects. DISCUSSION: Pramlintide use appeared to be safe in the absence of diabetes. The biomarker changes as a result of the pramlintide challenge, which distinguished AD from control subjects and mild cognitive impairment.
RESUMEN
Amylin is an important gut-brain axis hormone. Since amylin and amyloid-ß peptide (Aß) share similar ß sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Aß in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Aß and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Aß. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an amylin receptor antagonist successfully antagonized some protective effects of amylin in vivo, suggesting that the protective effects of amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that amylin electively suppresses activation of the CDK5 pathway by Aß. Treatment with amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases.
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Enfermedad de Alzheimer/patología , Encéfalo/patología , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/fisiopatología , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/efectos de los fármacos , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/química , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Ligandos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Mutación/genética , Fragmentos de Péptidos/uso terapéutico , Presenilina-1/genética , Presenilina-1/metabolismo , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/antagonistas & inhibidores , Memoria Espacial/efectos de los fármacos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Findings from Alzheimer's disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-ß (Aß) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aß serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aß transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aß transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aß efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aß across the BBB. Collectively, our findings indicated that amylin induced Aß brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium.
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Péptidos beta-Amiloides/metabolismo , Barrera Hematoencefálica/metabolismo , Permeabilidad Capilar/fisiología , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Animales , Barrera Hematoencefálica/efectos de los fármacos , Técnicas de Cultivo de Célula , Células Cultivadas , Fármacos del Sistema Nervioso Central/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Femenino , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/farmacología , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad , Ratones Transgénicos , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/antagonistas & inhibidores , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/genética , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/metabolismo , Receptores de LDL/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Uncovering genetic variation through resequencing is limited by the fact that only sequences with similarity to the reference genome are examined. Reference genomes are often incomplete and cannot represent the full range of genetic diversity as a result of geographical divergence and independent demographic events. To more comprehensively characterize genetic variation of pigs (Sus scrofa), we generated de novo assemblies of nine geographically and phenotypically representative pigs from Eurasia. By comparing them to the reference pig assembly, we uncovered a substantial number of novel SNPs and structural variants, as well as 137.02-Mb sequences harboring 1737 protein-coding genes that were absent in the reference assembly, revealing variants left by selection. Our results illustrate the power of whole-genome de novo sequencing relative to resequencing and provide valuable genetic resources that enable effective use of pigs in both agricultural production and biomedical research.
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Mapeo Contig/métodos , Genómica/métodos , Polimorfismo Genético , Análisis de Secuencia de ADN/métodos , Porcinos/genética , Animales , Mapeo Contig/normas , Genoma , Genómica/normas , Análisis de Secuencia de ADN/normasRESUMEN
Our recent study has demonstrated that peripheral amylin treatment reduces the amyloid pathology in the brain of Alzheimer's disease (AD) mouse models, and improves their learning and memory. We hypothesized that the beneficial effects of amylin for AD was beyond reducing the amyloids in the brain, and have now directly tested the actions of amylin on other aspects of AD pathogenesis, especially neuroinflammation. A 10-week course of peripheral amylin treatment significantly reduced levels of cerebral inflammation markers, Cd68 and Iba1, in amyloid precursor protein (APP) transgenic mice. Mechanistic studies indicated the protective effect of amylin required interaction with its cognate receptor because silencing the amylin receptor expression blocked the amylin effect on Cd68 in microglia. Using weighted gene co-expression network analysis, we discovered that amylin treatment influenced two gene modules linked with amyloid pathology: 1) a module related to proinflammation and transport/vesicle process that included a hub gene of Cd68, and 2) a module related to mitochondria function that included a hub gene of Atp5b. Amylin treatment restored the expression of most genes in the APP cortex toward levels observed in the wild-type (WT) cortex in these two modules including Cd68 and Atp5b. Using a human dataset, we found that the expression levels of Cd68 and Atp5b were significantly correlated with the neurofibrillary tangle burden in the AD brain and with their cognition. These data suggest that amylin acts on the pathological cascade in animal models of AD, and further supports the therapeutic potential of amylin-type peptides for AD.
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Enfermedad de Alzheimer/complicaciones , Antiinflamatorios/uso terapéutico , Corteza Cerebral/efectos de los fármacos , Encefalitis , Regulación de la Expresión Génica/efectos de los fármacos , Polipéptido Amiloide de los Islotes Pancreáticos/uso terapéutico , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Proteínas de Unión al Calcio/metabolismo , Línea Celular Transformada , Modelos Animales de Enfermedad , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Encefalitis/patología , Regulación de la Expresión Génica/genética , Humanos , Lipopolisacáridos/farmacología , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Microglía/efectos de los fármacos , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Ovillos Neurofibrilares/metabolismo , Ovillos Neurofibrilares/patología , Receptores de Polipéptido Amiloide de Islotes Pancreáticos/metabolismoRESUMEN
Age is the major risk factor for developing Alzheimer's disease (AD), and modifying age-related factors may help to delay the onset of the disease. The goal of this study was to investigate the relationship between age and the metabolic factors related to the risk of developing AD. The concentrations of insulin, amylin, and amyloid-ß peptide (Aß) in plasma were measured. We further measured the activity of serum Aß degradation by using fluorescein- and biotin-labeled Aß40. Apolipoprotein E4 allele (ApoE4) and cognitive impairment were characterized. Subjects were divided into three age groups: 60-70, 70-80, and ≥80 years old. We found that the older the subjects, the lower the concentration of insulin (pâ=â0.001) and the higher the concentration of Aß1-40 (pâ=â0.004) in plasma. However, age was not associated with the concentration of another pancreatic peptide, amylin, and only marginally with Aß1-42. These relationships remained in the absence of diabetes, cardiovascular disease, and stroke, and regardless of the presence of ApoE4 and cognitive impairment. Both age and ApoE4 were inversely associated with, while insulin was positively associated with, the activities of Aß degradation in serum. Our study suggested that low concentration of insulin and high concentration of Aß40 are aging factors related to the risk of AD.
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Envejecimiento , Enfermedad de Alzheimer/sangre , Péptidos beta-Amiloides/sangre , Apolipoproteína E4/sangre , Trastornos del Conocimiento/sangre , Insulina/sangre , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Fragmentos de Péptidos/sangre , Distribución por Edad , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios Transversales , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
BACKGROUND: Amyloid-associated depression is associated with cognitive impairment cross sectionally. This follow-up study was to determine the relationship between amyloid-associated depression and the development of Alzheimer's disease (AD). METHODS: Two hundred and twenty three subjects who did not have dementia at baseline were given a repeat cognitive evaluation for incident AD. Depression was defined by having a Center for Epidemiological Studies Depression (CES-D) score ≥ 16, and non-amyloid vs. amyloid-associated depression by having a low vs. high plasma amyloid-ß peptide 40 (Aß40)/Aß42 ratio. Apolipoprotein E (ApoE) genotype was determined, and antidepressant usage was documented. RESULTS: Fifteen subjects developed AD (7%) after an average follow-up time of 6.2 years. While none of those with non-amyloid depression developed AD, 9% of those with amyloid-associated depression developed AD. Further, among those with amyloid-associated depression, ApoE4 carriers tended to have a higher risk of AD than ApoE4 non-carriers (40% vs. 4%, p = 0.06). In contrast, 8% of those who did not have depression at baseline developed AD, but ApoE4 carriers and non-carriers did not show a difference in the AD risk. After adjusting for age, the interaction between ApoE4 and amyloid-associated depression (ß = +0.113, SE = 0.047, P = 0.02) and the interaction between ApoE4 and antidepressant use (ß = +0.174, SE = 0.064, P = 0.007) were associated with the AD risk. CONCLUSIONS: Amyloid-associated depression may be prodromal depression of AD especially in the presence of ApoE4. Future studies with a larger cohort and a longer follow-up are warranted to further confirm this conclusion.
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Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/sangre , Apolipoproteína E4/genética , Trastorno Depresivo/sangre , Anciano , Anciano de 80 o más Años , Alelos , Análisis de Varianza , Trastornos del Conocimiento/sangre , Trastornos del Conocimiento/psicología , Trastorno Depresivo/complicaciones , Trastorno Depresivo/genética , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana EdadRESUMEN
Amylin, a gut-brain axis hormone, and amyloid-beta peptides (Aß), a major component of the Alzheimer's disease (AD) brain, share several features, including similar ß-sheet secondary structures, binding to the same receptor and being degraded by the same protease, insulin degrading enzyme (IDE). However, while amylin readily crosses the blood brain barrier (BBB) and mediates several activities including improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reaction and perhaps enhancing neural regeneration, Aß has no known physiological functions. Thus, abundant Aß in the AD brain could block or interfere with the binding of amylin to its receptor and hinder its functions. Recent studies using animal models for AD demonstrate that amylin and its analog reduce the AD pathology in the brain and improve cognitive impairment in AD. Given that, in addition to amyloid plaques and neurofibrillary tangles, perturbed cerebral glucose metabolism and cerebrovascular damage are the hallmarks of the AD brain, we propose that giving exogenous amylin type peptides have the potential to become a new avenue for the diagnosis and therapeutic of AD. Although amylin's property of self-aggregation may be a limitation to developing it as a therapeutic for AD, its clinical analog, pramlintide containing 3 amino acid differences from amylin, does not aggregate like human amylin, but more potently mediates amylin's activities in the brain. Pramlintide is an effective drug for diabetes with a favorable profile of safety. Thus a randomized, double-blind, placebo-controlled clinical trial should be conducted to examine the efficacy of pramlintide for AD. This review summarizes the knowledge and findings on amylin type peptides and discuss pros and cons for their potential for AD.
RESUMEN
Our recent study reported that amylin, a pancreatic peptide that readily crosses the blood-brain barrier, improves learning and memory in Alzheimer's disease mouse models. However, the relationship between peripheral amylin and cognition in humans is unknown. In this follow-up study, using a cross-sectional, homebound elderly population, improvement in cognitive function with increasing quartiles of plasma amylin was suggested by positive association with verbal memory (p = 0.0002) and visuoconstruction tasks (p = 0.004), and inverse association with timed measures of attention (p < 0.0001) and executive function (p = 0.04). After adjusting for demographic information, apolipoprotein E4 allele, diabetes, stroke, kidney function, and lipid profile, log10 of plasma amylin remained associated with these cognitive domains. In contrast, plasma amyloid-ß peptide was not associated with these specific cognitive domains. Our study suggests that peripheral amylin may be protective for cognitive decline, especially in the domains affected by Alzheimer's disease.
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Cognición/fisiología , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Anciano , Anciano de 80 o más Años , Amiloidosis Familiar/sangre , Apolipoproteínas E/genética , Atención/fisiología , Planificación en Salud Comunitaria , Distrofias Hereditarias de la Córnea/sangre , Femenino , Genotipo , Evaluación Geriátrica , Servicios de Atención de Salud a Domicilio/estadística & datos numéricos , Humanos , Aprendizaje/fisiología , Masculino , Escala del Estado Mental , Pruebas Neuropsicológicas , Conducta Verbal/fisiologíaRESUMEN
Amylin, a pancreatic peptide that readily crosses the blood brain barrier (BBB), and amyloid-beta peptide (Aß), the main component of amyloid plaques and a major component of Alzheimer's disease (AD) pathology in the brain, share several features. These include having similar ß-sheet secondary structures, binding to the same receptor, and being degraded by the same protease. Thus, amylin may be associated with Aß, but the nature of their relationship remains unclear. In this study, we used human samples to study the relationship between plasma amylin and Aß in the context of the apolipoprotein E alleles (ApoE). We found that concentrations of Aß1-42 (P<0.0001) and Aß1-40 (P<0.0001) increased with each quartile increase of amylin. Using multivariate regression analysis, the study sample showed that plasma amylin was associated with Aß1-42 (ß =â+0.149, SE = 0.025, P<0.0001) and Aß1-40 (ß =â+0.034, SE = 0.016, P = 0.04) as an outcome after adjusting for age, gender, ethnicity, ApoE4, BMI, diabetes, stroke, kidney function and lipid profile. This positive association between amylin and Aß1-42 in plasma was found regardless of the ApoE genotype. In contrast, the relationship between amylin and Aß1-40 in plasma seen in ApoE4 non-carriers disappeared in the presence of ApoE4. Using AD mouse models, our recent study demonstrates that intraperitoneal (i.p.) injection of synthetic amylin enhances the removal of Aß from the brain into blood, thus resulting in increased blood levels of both amylin and Aß. The positive association between amylin and Aß, especially Aß1-42, in human blood samples is probably relevant to the findings in the AD mouse models. The presence of ApoE4 may attenuate amylin's capacity to remove Aß, especially Aß1-40, from the AD brain.
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Alelos , Péptidos beta-Amiloides/sangre , Apolipoproteína E4/genética , Polipéptido Amiloide de los Islotes Pancreáticos/sangre , Anciano , Animales , Biomarcadores/sangre , Femenino , Humanos , Masculino , Ratones , Análisis Multivariante , Análisis de RegresiónRESUMEN
BACKGROUND: Plasma amylin is positively associated with cognitive function in humans. Amylin treatment improves memory in Alzheimer's mouse models. However, the relationship between plasma amylin, diabetes and cognition is not clear. OBJECTIVES: In this study we examined the concentration of plasma amylin, its relationship with diabetes and cognition. MATERIAL AND METHOD: A cross-sectional, homebound elderly population with data of plasma amylin under fasting condition and cognitive measurements was used. RESULTS: We found that subjects with a long and chronic duration of diabetes were more likely to take insulin treatment and have reduced secretion of amylin. Compared to non-diabetics, diabetic subjects without insulin treatment had a higher concentration, but those with insulin treatment had a lower concentration, of plasma amylin [median (Q1, Q3): 20 (11.0, 36.2) vs. 25.2 (13.2, 50.6) vs. 15.0 (4.9, 33.8), p<0.0001]. In the whole sample vs. in the absence of diabetes, plasma amylin was positively associated with logical memory delayed recall (ß= +0.61, SE=0.25, p=0.02 vs. ß=+0.80, SE=0.33, p=0.02) and block design (ß=+0.62, SE=0.24, p=0.009 vs. ß=+0.93, SE=0.31, p=0.003), and negatively associated with Trailmaking A scores (ß= -6.21, SE=1.55, p<0.0001 vs. ß=-7.51, SE=1.95, p=0.0001) and Trailmaking B (ß= -4.32, SE=2.13, p=0.04 vs. ß= -5.86, SE=2.73, p=0.04). All these relationships disappeared in the presence of diabetes regardless the treatment. CONCLUSION: This study suggests that secretion of amylin by pancreas compensates and then deteriorates depending on the duration of diabetes. Amylin's activities for cognition are impaired in the presence of diabetes.
RESUMEN
OBJECTIVE: The effect of angiotensin converting enzyme (ACE) inhibitors on Alzheimer disease (AD) remains unclear, with conflicting results reported. We studied the interaction of the Apolipoprotein E (ApoE) genotype and ACE inhibitors on AD. METHODS: This was a cross-sectional study of homebound elderly with an AD diagnosis and documentation of medications taken. ApoE genotype was determined. RESULTS: A total of 355 subjects with status on ApoE alleles and cognitive diagnoses were studied. The average age (mean ± SD) of this population was 73.3 ± 8.3 years old, and 73% were female. Cross-sectionally, there was no difference in the number of AD cases between ApoE4 carriers and ApoE4 non-carriers or between ACE inhibitor users and non-users in the homebound elderly. ApoE4 carriers treated with ACE inhibitors, however, had more diagnoses of AD compared with those who did not have the treatment (28% versus 6%, p = 0.01) or ApoE4 non-carriers treated with an ACE inhibitor (28% versus 10%, p = 0.03). ACE inhibitor use was associated with AD diagnosis only in the presence of an E4 allele. Using multivariate logistic regression analysis, we found that in diagnosed AD cases there was a significant interaction between ApoE4 and ACE inhibitor use (odds ratio: 20.85; 95% confidence interval: 3.08-140.95; p = 0.002) after adjusting for age, sex, ethnicity, and education. CONCLUSION: The effects of ACE inhibitors on AD may be different depending on ApoE genotype. A prospective study is needed to determine whether ACE inhibitor use accelerates or poorly delays AD development in ApoE4 carriers compared with ApoE4 non-carriers.
Asunto(s)
Alelos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Apolipoproteína E4/genética , Anciano , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/psicología , Estudios Transversales , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Peptidil-Dipeptidasa A/sangreRESUMEN
Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer's disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer's Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 test: 13% versus 27%, p < 0.0001) had lower incidence of AD compared with those who had not been taking an ACE inhibitor. In contrast, in the presence of ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p < 0.0001) still remained inversely associated with a risk of developing AD in ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Apolipoproteína E4/genética , Farmacogenética , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Genotipo , Humanos , Modelos Logísticos , Estudios Longitudinales , Masculino , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Small vessel (SV) and large vessel (LV) brain infarcts are distinct pathologies. Using a homebound elderly sample, the numbers of either infarct subtypes were similar between those apolipoprotein E4 allele (ApoE4) carriers (n = 80) and noncarriers (n = 243). We found that the higher the number of SV infarcts, but not LV infarcts, a participant had, the higher the activity of substrate V degradation in serum especially among ApoE4 carriers (ß = +0.154, SE = 0.031, P < .0001) after adjusting for the confounders. Since substrate V degradation could be mediated by insulin-degrading enzyme (IDE) or/and angiotensin-converting enzyme (ACE), but no relationship was found between SV infarcts and specific ACE activities, blood IDE may be a useful biomarker to distinguish the brain infarct subtypes. Insulin-degrading enzyme in blood may also imply an important biomarker and a pathological event in Alzheimer disease through SV infarcts in the presence of ApoE4.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Infarto Encefálico/enzimología , Anciano , Anciano de 80 o más Años , Alelos , Biomarcadores/metabolismo , Infarto Encefálico/diagnóstico , Infarto Encefálico/genética , Estudios Transversales , Demencia/diagnóstico , Femenino , Heterocigoto , Humanos , Insulisina/fisiología , Imagen por Resonancia Magnética , Masculino , Péptido Hidrolasas/metabolismoRESUMEN
Sporadic Alzheimer's disease (AD) patients have low amyloid-ß peptide (Aß) clearance in the central nervous system. The peripheral Aß clearance may also be important but its role in AD remains unclear. We aimed to study the Aß degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aß. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aß degradation may be important for the AD pathogenesis. More studies are needed to specify each Aß degrading protease in blood as a useful biomarker and a possible treatment target for AD.