Description
MicroRNAs miR-155 and miR-146a modulate inflammation in Alzheimer's Disease
Macarena S. Aloi1,2, Katherine E. Prater2, Bryce Sopher2, Stephanie Davidson2, Suman Jayadev1,2 and Gwenn A. Garden1,2
Department of Pathology1, Department of Neurology2, University of Washington, School of Medicine
Alzheimer's Disease (AD) is a progressive age-related neurodegenerative disorder characterized by the accumulation of extracellular amyloid beta (Aβ) as well as CNS and systemic inflammation. Innate immune cells like CNS resident microglia and circulating monocytes use microRNAs to rapidly respond to inflammatory signals, such as Aβ exposure. MicroRNA (miRNA) profiles are altered in tissue, circulating monocytes, and serum of AD cases. MiR-155 and miR-146a are two miRNAs that modulate the phasic inflammatory responses of innate immune cells. In vivo miR-146a deletion leads to an accelerated aging phenotype, which is abrogated by conditional deletion of miR-155. MiR-155 and miR-146a are known to influence the transition between phases of the inflammatory response, however their precise roles in AD remain unknown. We hypothesize that miR-155 and miR-146a participate in AD pathophysiology by modulating Aβ equilibrium and the functions of inflammatory cells. Using cultured neonatal microglia, we observed that modulation of miR-155 and miR-146a expression impacts the internalization and degradation of fibrillar Aβ. We generated trigenic APP/PS1 AD mouse models to induce CX3CR1 driven Cre-mediated deletion of floxed miR-155 alleles in microglia alone or in both microglia and circulating monocytes. Microglia were isolated by ex vivo FACS and miR-155 deletion was assessed by endpoint PCR. We observed deletion of miR-155 floxed alleles and substantially reduced miR-155 expression. Changes in inflammatory gene expression in microglia at 6 and 9 months of age were assessed by qPCR. Targets of miR-155 including cMAF, CSF1R, SOCS1, and SHIP1 were upregulated in microglia isolated from 6 month old animals. Concentrations of soluble and insoluble Aβ in cortical and hippocampal lysates were assessed using Luminex at 6 and 9 month of age. Our results thus far support the hypothesis that miR-155 deletion alters innate immune gene expression and Aβ equilibrium in an AD mouse model, further elucidating the molecular pathways regulating neuroinflammation in AD.
NIH Grants: R01 AG051437-01, T32-AG052354, T32-GM95412 and the HHMI Gilliam Fellowship for Advanced Studies.