AD-linked R47H-TREM2mutation induces disease-enhancing microglial states via AKT hyperactivation

Abstract

R47H- TREM2 mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

“…Notably, a similar sex difference has also been observed in Trem2 KO mice crossed with APP1/PS1 mice ( (Delizannis et al, 2021); females have more plaques) and human TREM2*R47H cDNA mice crossed to the PS19 tauopathy model (females have more inflammatory gene expression and spatial memory deficits), as well as transcriptomic analysis of R47H-carrying AD patients ( (Sayed et al, 2021); females upregulating immune activation pathways while males upregulate metabolic and adenosine triphosphate pathway). No sex difference was observed by 12 months of age, but plaque density was increased by the presence of the R47H mutation, while both soluble and insoluble Aβ levels are also increased.…”

“…Utilizing a BAC, transgenic mice expressing human common variant (CV) and R47H variants of TREM2 have been crossed with TREM2 KO 5xFAD mice, with the resultant phenotype phenocopying TREM2 KO, therefore suggesting TREM2 *R47H variant is a loss-of-function allele of TREM2 (Song et al, 2018). As an extension of this approach, heterozygous human TREM2 *R47H and CV cDNA has also been knocked into the mouse Trem2 locus (Sayed et al, 2021), such that animals express human TREM2 , but without the full complement of regulatory machinery. Crossing of these mice with the PS19 mouse model of tauopathy found that the R47H variant exacerbates damage and inflammation and does not function as a loss of function variant (Sayed et al, 2021), unlike similar crosses of PS19 mice with the BAC TREM2 *R47H model which actually protected against microglia activation and subsequent neurodegeneration (Gratuze et al, 2020), as did crosses with PS19 mice and TREM2 KO mice (Leyns et al, 2017; Sayed et al, 2018).…”

“…As an extension of this approach, heterozygous human TREM2 *R47H and CV cDNA has also been knocked into the mouse Trem2 locus (Sayed et al, 2021), such that animals express human TREM2 , but without the full complement of regulatory machinery. Crossing of these mice with the PS19 mouse model of tauopathy found that the R47H variant exacerbates damage and inflammation and does not function as a loss of function variant (Sayed et al, 2021), unlike similar crosses of PS19 mice with the BAC TREM2 *R47H model which actually protected against microglia activation and subsequent neurodegeneration (Gratuze et al, 2020), as did crosses with PS19 mice and TREM2 KO mice (Leyns et al, 2017; Sayed et al, 2018). In addition to these humanized approaches, several TREM2 *R47H mouse models have been generated via CRISPR/Cas9 technology and have reported similar findings as Trem2 KO mice (Cheng-Hathaway et al, 2018; Xiang et al, 2018).…”

“…These include SPI1, BIN1, GRN, CD33 (Carrasquillo et al, 2010;Jiang et al, 2014;Lambert et al, 2013;Tansey et al, 2018)), as well as coding variants in ABI3 and PLCG2 (Conway et al, 2018;Sims et al, 2017). During AD, microglia mount an inflammatory response to Aβ plaques, as evidenced by findings in both human AD brains and animal models of the disease (Leng and Edison, 2021;Sayed et al, 2021). Accumulating evidence implicates microglia in several ADrelated processes including plaque formation and growth (Spangenberg et al, 2019), plaque compaction (Casali et al, 2020;Spangenberg et al, 2019), constituting a protective barrier against dystrophic neurites (Condello et al, 2015), promoting or preventing development and spreading of Tau pathology (Shi et al, 2019), cerebral amyloid angiopathy (Spangenberg et al, 2019), destruction of perineuronal nets (Arreola et al, 2021;Crapser et al, 2020), as well as Tran et.…”

Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity

“…Although we detected moderate enrichment of the PI3K-AKT signaling pathway in APOE3 iMGLs exposed to spheroid conditioned media (APOE3 vs. APOE3+CM) (Supplemental Table 1), we observed a comparable increase in the induction levels of AKT serine/threonine kinase 1 (AKT1) in APOE4 iMGLs +CM in comparison to APOE3 iMGLs +CM (Supplementary Figure S2F). AKT hyperactivation has been recently reported in microglia of AD patients, and pharmacological inhibition of AKT in murine microglia was found to reverse inflammatory signatures (Sayed et al, 2021). Also of note regarding the relationship between calcium influx and lipid signaling is the upregulation of ARL4C (Also known as ARL7), the most overall enriched DEG we identified in CM-evoked transcripts in APOE3 (Log2 fold-change = 1.87, FDR 4.05x10 -71 ) and even more so in APOE4 (Log2 fold-change = 2.43, FDR 6.20x10 -191 ) (Figure 3B).…”