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1.
Nat Commun ; 13(1): 6384, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36289231

RESUMO

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.


Assuntos
Transtornos Cognitivos , Síndrome de Down , Camundongos , Animais , Síndrome de Down/genética , Síndrome de Down/metabolismo , Variações do Número de Cópias de DNA/genética , Modelos Animais de Doenças , Transtornos Cognitivos/genética , Cromatina/genética , Camundongos Transgênicos
2.
J Alzheimers Dis ; 72(4): 1323-1339, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743995

RESUMO

Alzheimer's disease (AD) has several hallmark features including amyloid-ß (Aß) plaque deposits and neuronal loss. Here, we characterized Aß plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6-9-month-old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescence staining to compare three regions in the frontal cortex-prelimbic (PrL), cingulate (Cg, including Cg1 and Cg2), and secondary motor (M2) cortices-along with primary somatosensory (S1) cortex. We quantified the density of Aß plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal regions compared to S1. We also found layer- and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (-50%) and M2 (-39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about Aß deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Lobo Frontal/patologia , Neurônios/patologia , Parvalbuminas/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia
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