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

Summary Understanding how high-risk individuals are protected from Alzheimer’s 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 NFκB 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 oAβ42. This was associated with reduced activation of JNK and NFκB pathways in response to these stimuli. Pharmacological inhibition of JNK or NFκB signaling phenocopied SH3RF3 knockdown. We also found PSEN1G206A microglia had reduced inflammatory response to oAβ42. 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. Competing Interest Statement The authors have declared no competing interest. Footnotes This version includes 1 new main body figure, 2 new main body tables, and 1 supplemental table regarding additional SH3RF3 genetic variants that are protective against Alzheimer's disease. Statistical analysis for some main body and supplemental figures was done differently and bar graphs present that data in a slightly different way, although all results remained statistical that were so in the previous version. Former Figure 5 became the graphical abstract.