Reduced <i>SH3RF3</i> May Protect Against Alzheimer's Disease by Lowering Microglial Pro‐Inflammatory Responses via Modulation of <scp>JNK</scp> and <scp>NFkB</scp> Signaling

ABSTRACT 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 PSEN1 G206A mutation. SH3RF3 acts as a JNK pathway scaffold and activates NFκB signaling. While the 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 PSEN1 G206A microglia had a reduced inflammatory response to oAβ42. Thus, further reduction of microglial inflammatory responses in PSEN1 G206A mutant carriers by protective variants in SH3RF3 might reduce the link between amyloid and neuroinflammation to subsequently delay the onset of AD.