Idioma:

Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models

Lee, C.Y. Daniel ; Daggett, Anthony ; Gu, Xiaofeng ; Jiang, Lu-Lin ; Langfelder, Peter ; Li, Xiaoguang ; Wang, Nan ; Zhao, Yingjun ; Park, Chang Sin ; Cooper, Yonatan ; Ferando, Isabella ; Mody, Istvan ; Coppola, Giovanni ; Xu, Huaxi ; Yang, X. William

Neuron (Cambridge, Mass.), 2018-03, Vol.97 (5), p.1032-1048.e5 [Periódico revisado por pares]

United States: Elsevier Inc

Texto completo disponível

Citações Citado por

Enviar para

Título:
Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models
Autor: Lee, C.Y. Daniel ; Daggett, Anthony ; Gu, Xiaofeng ; Jiang, Lu-Lin ; Langfelder, Peter ; Li, Xiaoguang ; Wang, Nan ; Zhao, Yingjun ; Park, Chang Sin ; Cooper, Yonatan ; Ferando, Isabella ; Mody, Istvan ; Coppola, Giovanni ; Xu, Huaxi ; Yang, X. William
Assuntos: Alzheimer Disease - genetics ; Alzheimer Disease - pathology ; Alzheimer's disease ; amyloid plaque ; Animal models ; Animals ; Animals, Newborn ; Artificial chromosomes ; BAC ; Bacterial artificial chromosomes ; Cell activation ; Cells, Cultured ; Cellular Reprogramming Techniques - methods ; Dementia ; Disease ; Disease Models, Animal ; Dystrophy ; Female ; Gene dosage ; Gene Dosage - genetics ; Gene expression ; Genomes ; Genotype & phenotype ; Health risk assessment ; Humans ; Hypothesis testing ; Male ; Membrane Glycoproteins - biosynthesis ; Membrane Glycoproteins - genetics ; Memory - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia ; Microglia - pathology ; Microglia - physiology ; mouse ; neuroinflammation ; Neurons ; Organ Culture Techniques ; Pathogenesis ; Phagocytes ; Phagocytosis ; Phenotype ; Proteins ; Receptors, Immunologic - biosynthesis ; Receptors, Immunologic - genetics ; reprogramming ; RNA-sequencing ; Rodents ; Transgenic animals ; Transgenic mice ; TREM2
É parte de: Neuron (Cambridge, Mass.), 2018-03, Vol.97 (5), p.1032-1048.e5
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
These authors contributed equally
Descrição: Variants of TREM2 are associated with Alzheimer’s disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models. •Elevating TREM2 gene dosage altered microglial morphology and interaction with Aβ•Increasing TREM2 gene dosage reprograms microglial responsivity in AD mouse brains•Transcriptomic profiling identified three groups of TREM2 gene-dosage-dependent genes•Extra TREM2 gene dosage ameliorates neuropathology and memory deficits in AD mice Augmenting TREM2 gene dosage in AD mouse models leads to reduced amyloid burden and neuropathology and improved memory performance. Gene expression profiling reveals a reprogrammed disease-associated microglial response that may underlie the phenotypic improvement in AD models.
Editor: United States: Elsevier Inc
Idioma: Inglês

Links

View this record in MEDLINE/PubMed

Voltar para lista de resultados

Realização: Logos de Redes Sociais:

Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models

Lee, C.Y. Daniel ; Daggett, Anthony ; Gu, Xiaofeng ; Jiang, Lu-Lin ; Langfelder, Peter ; Li, Xiaoguang ; Wang, Nan ; Zhao, Yingjun ; Park, Chang Sin ; Cooper, Yonatan ; Ferando, Isabella ; Mody, Istvan ; Coppola, Giovanni ; Xu, Huaxi ; Yang, X. William

United States: Elsevier Inc

Buscando em bases de dados remotas. Favor aguardar.