Reduced SH3RF3 may protect against Alzheimer's disease by lowering microglial pro-inflammatory responses via modulation of JNK and NFkB signaling

Understanding how high-risk individuals are protected from Alzheimers disease (AD) may illuminate potential therapeutic targets. We identified protective genetic variants in SH3RF3/POSH2 that delayed the onset of AD among individuals carrying the PSEN1G206A mutation. SH3RF3 acts as a JNK pathway scaffold and activates NF{kappa}B signaling. While effects of SH3RF3 knockdown in human neurons were subtle, including decreased ptau S422, knockdown in human microglia significantly reduced inflammatory cytokines in response to either a viral mimic or oA{beta}42. This was associated with reduced activation of JNK and NF{kappa}B pathways in response to these stimuli. Pharmacological inhibition of JNK or NF{kappa}B signaling phenocopied SH3RF3 knockdown. We also found PSEN1G206A microglia had reduced inflammatory response to oA{beta}42. Thus, further reduction of microglial inflammatory responses in PSEN1G206A mutant carriers by protective variants in SH3RF3 might reduce the link between amyloid and neuroinflammation to subsequently delay the onset of AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/600281v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@46f29org.highwire.dtl.DTLVardef@11e1dfeorg.highwire.dtl.DTLVardef@43311eorg.highwire.dtl.DTLVardef@14de11f_HPS_FORMAT_FIGEXP M_FIG C_FIG