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Peer-reviewedCC BYGlia

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

  • Ronak Patel1
  • Rong Cheng2
  • Christopher L. Cardona3
  • Ellen Angeles1
  • Gunjandeep Singh1
  • Sabrina Miller4,1
  • Archana Ashok1
  • Andrew F. Teich2,3,1
  • Angel L. Piriz2,5,1
  • Aleyda Maldonado6
  • Ivonne Z. Jiménez‐Velázquez6
  • Richard P Mayeux7,2,5,1
2 more authors
  • Joseph H. Lee7,2,5,1
  • Andrew A. Sproul3,1
7 affiliations
  1. 1Taub Institute for Research on Alzheimer's Disease and the Aging Brain Columbia University Irving Medical Center (CUIMC) New York New York USA
  2. 2Department of Neurology CUIMC New York New York USA
  3. 3Department of Pathology and Cell Biology CUIMC New York New York USA
  4. 4East Side Community School New York New York USA
  5. 5G.H. Sergievsky Center CUIMC New York New York USA
  6. 6Department of Internal Medicine, Geriatric Division University of Puerto Rico School of Medicine San Juan Puerto Rico USA
  7. 7Department of Epidemiology CUIMC New York New York USA
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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.

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Cite

BibTeXRIS
BibTeX
@article{patel2026reduced,
  title = {{Reduced SH3RF3 May Protect Against Alzheimer's Disease by Lowering Microglial Pro‐Inflammatory Responses via Modulation of JNK and NFkB Signaling}},
  author = {Ronak Patel and Rong Cheng and Christopher L. Cardona and Ellen Angeles and Gunjandeep Singh and Sabrina Miller and Archana Ashok and Andrew F. Teich and Angel L. Piriz and Aleyda Maldonado and Ivonne Z. Jiménez‐Velázquez and Richard P Mayeux and Joseph H. Lee and Andrew A. Sproul},
  journal = {Glia},
  year = {2026},
  month = may,
  doi = {10.1002/glia.70165},
  url = {https://doi.org/10.1002/glia.70165},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Reduced SH3RF3 May Protect Against Alzheimer's Disease by Lowering Microglial Pro‐Inflammatory Responses via Modulation of JNK and NFkB Signaling
AU  - Ronak Patel
AU  - Rong Cheng
AU  - Christopher L. Cardona
AU  - Ellen Angeles
AU  - Gunjandeep Singh
AU  - Sabrina Miller
AU  - Archana Ashok
AU  - Andrew F. Teich
AU  - Angel L. Piriz
AU  - Aleyda Maldonado
AU  - Ivonne Z. Jiménez‐Velázquez
AU  - Richard P Mayeux
AU  - Joseph H. Lee
AU  - Andrew A. Sproul
PY  - 2026
DA  - 2026/05/27
JO  - Glia
DO  - 10.1002/glia.70165
UR  - https://doi.org/10.1002/glia.70165
AB  - 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.
SN  - 0894-1491
SN  - 1098-1136
ER  -