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

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 i...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Neuron (Cambridge, Mass.) Ročník 97; číslo 5; s. 1032
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 07.03.2018
Témata:	Alzheimer Disease - genetics Alzheimer Disease - pathology Animals Animals, Newborn Cells, Cultured Cellular Reprogramming Techniques - methods Disease Models, Animal Female Gene Dosage - genetics Humans Male Membrane Glycoproteins - biosynthesis Membrane Glycoproteins - genetics Memory - physiology Mice Mice, Inbred C57BL Mice, Transgenic Microglia - pathology Microglia - physiology Organ Culture Techniques Phenotype Receptors, Immunologic - biosynthesis Receptors, Immunologic - genetics RNA-sequencing reprogramming mouse Alzheimer’s disease BAC neuroinflammation TREM2 amyloid plaque gene dosage microglia
ISSN:	1097-4199, 1097-4199
On-line přístup:	Zjistit podrobnosti o přístupu
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4199 1097-4199
DOI:	10.1016/j.neuron.2018.02.002