RESUMO
Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Feminino , Doença de Alzheimer/genética , Cromossomos Humanos Y/genética , Estudo de Associação Genômica Ampla , Mosaicismo , Fatores de Risco , Disfunção Cognitiva/genética , Proteínas tau/genética , Biomarcadores , Peptídeos beta-Amiloides/genéticaRESUMO
Iron deficiency (ID) represents one of the most prevalent nutritional deficits, affecting almost two billion people worldwide. Gestational iron deprivation induces hypomyelination due to oligodendroglial maturation deficiencies and is thus a useful experimental model to analyze oligodendrocyte (OLG) requirements to progress to a mature myelinating state. A previous proteomic study in the adult ID brain by our group demonstrated a pattern of dysregulated proteins involved in the tricarboxylic acid cycle and mitochondrial dysfunction. The aim of the present report was to assess bioenergetics metabolism in primary cultures of OLGs and astrocytes (ASTs) from control and ID newborns, on the hypothesis that the regulation of cell metabolism correlates with cell maturation. Oxygen consumption and extracellular acidification rates were measured using a Seahorse extracellular flux analyzer. ID OLGs and ASTs both exhibited decreased spare respiratory capacity, which indicates that ID effectively induces mitochondrial dysfunction. A decrease in glycogen granules was observed in ID ASTs, and an increase in ROS production was detected in ID OLGs. Immunolabeling of structural proteins showed that mitochondrial number and size were increased in ID OLGs, while an increased number of smaller mitochondria was observed in ID ASTs. These results reflect an unfavorable bioenergetic scenario in which ID OLGs fail to progress to a myelinating state, and indicate that the regulation of cell metabolism may impact cell fate decisions and maturation.
Assuntos
Astrócitos , Deficiências de Ferro , Humanos , Proteômica , Oligodendroglia/metabolismo , Metabolismo Energético , MetabolomaRESUMO
Along the entire lifetime, Notch is actively involved in dynamic changes in the cellular architecture and function of the nervous system. It controls neurogenesis, the growth of axons and dendrites, synaptic plasticity, and ultimately neuronal death. The specific roles of Notch in adult brain plasticity and neurological disorders have begun to be unraveled in recent years, and pieces of experimental evidence suggest that Notch is operative in diverse brain pathologies including tumorigenesis, stroke, and neurological disorders such as Alzheimer's disease, Down syndrome, and multiple sclerosis. In this review, we will cover the recent findings of Notch signaling and neural dysfunction in adult human brain and discuss its relevance in the pathogenesis of diseases of the central nervous system.