Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer’s disease

Abstract

BackgroundThe 5XFAD early onset mouse model of Alzheimer’s disease (AD) is gaining momentum. Behavioral, electrophysiological and anatomical studies have identified age-dependent alterations that can be reminiscent of human AD. However, transcriptional changes during disease progression have not yet been investigated. To this end, we carried out a transcriptomic analysis on RNAs from the neocortex and the hippocampus of 5XFAD female mice at the ages of one, four, six and nine months (M1, M4, M6, M9).ResultsOur results show a clear shift in gene expression patterns between M1 and M4. At M1, 5XFAD animals exhibit region-specific variations in gene expression patterns whereas M4 to M9 mice share a larger proportion of differentially expressed genes (DEGs) that are common to both regions. Analysis of DEGs from M4 to M9 underlines the predominance of inflammatory and immune processes in this AD mouse model. The rise in inflammation, sustained by the overexpression of genes from the complement and integrin families, is accompanied by an increased expression of transcripts involved in the NADPH oxidase complex, phagocytic processes and IFN-γ related pathways.ConclusionsOverall, our data suggest that, from M4 to M9, sustained microglial activation becomes the predominant feature and point out that both detrimental and neuroprotective mechanisms appear to be at play in this model. Furthermore, our study identifies a number of genes already known to be altered in human AD, thus confirming the use of the 5XFAD strain as a valid model for understanding AD pathogenesis and for screening potential therapeutic molecules.

Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation

“…Upon injury, microglia rapidly proliferate, migrate to the lesion sites, recognize the pathogen, ramify, and mount an immune response (Ransohoff and Perry, 2009). In the brains of both AD patients and amyloid model mice, microglia are found to be closely associated with the amyloid plaques and exhibit an ‘activated’ pro-inflammatory phenotype (Frautschy, et al, 1998, Landel, et al, 2014, Lee and Landreth, 2010, Perlmutter, et al, 1990). As such, investigating the biological mechanisms that regulate microglial functions is essential for understanding the potential etiology and for developing future therapeutic strategies for AD.…”

Gene expression comparison reveals distinct basal expression of HOX members and differential TNF-induced response between brain- and spinal cord-derived microvascular endothelial cells

“…Biological interpretation of the transcriptomic data was performed using the Java/Perl software PredictSearch®, which has been previously described [14–16]. This software characterizes the pathways and functional networks in which the selected genes are involved.…”

The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

“…A working hypothesis is that defects in membrane protein processing that result from PS/γ-secretase absence could result in protein accumulation in the lysosome, causing lysosomal stress and activating TFEB, much like LSDs and chloroquine treatment [1,15]. In addition, the 5 ×FAD mouse model, which contains five familial mutations related to AD (including two mutations in PS1), demonstrates transcriptomic upregulation of TFEB targets [80]. In these cases, TFEB is activated in response to lysosomal dysfunction, but is insufficient to address accumulating autophagosomes containing partially degraded material.…”