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1.
Cell Rep ; 43(7): 114488, 2024 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-39002124

RESUMO

Neuroinflammation is a prominent feature of Alzheimer's disease (AD). Activated microglia undergo a reprogramming of cellular metabolism necessary to power their cellular activities during disease. Thus, selective targeting of microglial immunometabolism might be of therapeutic benefit for treating AD. In the AD brain, the levels of microglial hexokinase 2 (HK2), an enzyme that supports inflammatory responses by promoting glycolysis, are significantly increased. In addition, HK2 displays non-metabolic activities that extend its inflammatory role beyond glycolysis. The antagonism of HK2 affects microglial phenotypes and disease progression in a gene-dose-dependent manner. HK2 complete loss fails to improve pathology by exacerbating inflammation, while its haploinsufficiency reduces pathology in 5xFAD mice. We propose that the partial antagonism of HK2 is effective in slowing disease progression by modulating NF-κB signaling through its cytosolic target, IKBα. The complete loss of HK2 affects additional inflammatory mechanisms related to mitochondrial dysfunction.


Assuntos
Doença de Alzheimer , Progressão da Doença , Hexoquinase , Microglia , Hexoquinase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , Microglia/patologia , Camundongos , Humanos , NF-kappa B/metabolismo , Camundongos Transgênicos , Transdução de Sinais , Inibidor de NF-kappaB alfa/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Inflamação/patologia , Inflamação/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Glicólise/efeitos dos fármacos , Dosagem de Genes
2.
bioRxiv ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38370821

RESUMO

Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3' untranslated regions (3'-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3'UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3'-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption.

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