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1.
Commun Biol ; 5(1): 1074, 2022 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-36209301

RESUMEN

Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.


Asunto(s)
Enfermedad de Alzheimer , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Ceramidas , Clorhidrato de Fingolimod , Estudio de Asociación del Genoma Completo , Humanos , Ratones , Esfingolípidos/metabolismo , Esfingolípidos/uso terapéutico , Esfingomielinas/uso terapéutico
2.
Cell Rep ; 37(13): 110182, 2021 12 28.
Artículo en Inglés | MEDLINE | ID: mdl-34965419

RESUMEN

Whether and how the pathogenic disruptions in endosomal trafficking observed in Alzheimer's disease (AD) are linked to its anatomical vulnerability remain unknown. Here, we began addressing these questions by showing that neurons are enriched with a second retromer core, organized around VPS26b, differentially dedicated to endosomal recycling. Next, by imaging mouse models, we show that the trans-entorhinal cortex, a region most vulnerable to AD, is most susceptible to VPS26b depletion-a finding validated by electrophysiology, immunocytochemistry, and behavior. VPS26b was then found enriched in the trans-entorhinal cortex of human brains, where both VPS26b and the retromer-related receptor SORL1 were found deficient in AD. Finally, by regulating glutamate receptor and SORL1 recycling, we show that VPS26b can mediate regionally selective synaptic dysfunction and SORL1 deficiency. Together with the trans-entorhinal's unique network properties, hypothesized to impose a heavy demand on endosomal recycling, these results suggest a general mechanism that can explain AD's regional vulnerability.


Asunto(s)
Enfermedad de Alzheimer/patología , Encéfalo/patología , Endosomas/patología , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Transporte Vesicular/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/metabolismo , Estudios de Casos y Controles , Endosomas/metabolismo , Femenino , Humanos , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Neuroimagen , Transporte de Proteínas , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
3.
Nat Commun ; 8(1): 1464, 2017 11 13.
Artículo en Inglés | MEDLINE | ID: mdl-29133888

RESUMEN

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.


Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Apolipoproteína E4/genética , Corteza Entorrinal/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Envejecimiento , Animales , Apolipoproteína E3/genética , Ondas Encefálicas/fisiología , Metabolismo Energético/genética , Ácidos Grasos/biosíntesis , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Transgénicos
4.
PLoS One ; 10(12): e0145467, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26720273

RESUMEN

Alzheimer's disease (AD) is the major cause of dementia worldwide. The pharmacological activation of nuclear receptors (Liver X receptors: LXRs or Retinoid X receptors: RXR) has been shown to induce overexpression of the ATP-Binding Cassette A1 (ABCA1) and Apolipoprotein E (ApoE), changes that are associated with improvement in cognition and reduction of amyloid beta pathology in amyloidogenic AD mouse models (i.e. APP, PS1: 2tg-AD). Here we investigated whether treatment with a specific LXR agonist has a measurable impact on the cognitive impairment in an amyloid and Tau AD mouse model (3xTg-AD: 12-months-old; three months treatment). The data suggests that the LXR agonist GW3965 is associated with increased expression of ApoE and ABCA1 in the hippocampus and cerebral cortex without a detectable reduction of the amyloid load. We also report that most cells overexpressing ApoE (86±12%) are neurons localized in the granular cell layer of the hippocampus and entorhinal cortex. In the GW3965 treated 3xTg-AD mice we also observed reduction in astrogliosis and increased number of stem and proliferating cells in the subgranular zone of the dentate gyrus. Additionally, we show that GW3965 rescued hippocampus long term synaptic plasticity, which had been disrupted by oligomeric amyloid beta peptides. The effect of GW3965 on synaptic function was protein synthesis dependent. Our findings identify alternative functional/molecular mechanisms by which LXR agonists may exert their potential benefits as a therapeutic strategy against AD.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Receptores Nucleares Huérfanos/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Apolipoproteínas E/metabolismo , Benzoatos/farmacología , Benzoatos/uso terapéutico , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Biomarcadores/metabolismo , Proliferación Celular/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Trastornos del Conocimiento/complicaciones , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/fisiopatología , Proteínas de Unión al ADN , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Giro Dentado/patología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Técnica del Anticuerpo Fluorescente , Gliosis/complicaciones , Gliosis/patología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Receptores X del Hígado , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Ratones Transgénicos , Proteínas del Tejido Nervioso/metabolismo , Nestina/metabolismo , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Proteínas Nucleares/metabolismo , Receptores Nucleares Huérfanos/agonistas , Biosíntesis de Proteínas/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Proteínas tau/metabolismo
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