Abstract 1522 Characterization of tau species in plasma as a blood-based detection method for Alzheimer's Disease

Knockout Wwox-/-mice exhibit rapid aggregation of a brain protein cascade, commencing with TRAPPC6AD, TIAF1, and SH3GLB2, followed by tau and amyloid b within 2 weeks after birth.Zfra4-10 peptide restores memory loss in 9-month-old triple-transgenic mice for Alzheimer's disease (3xTg-AD) by halting the protein aggregation.Here, we determined how Zfra4-10 works.Circulating Zfra4-10, when polymerized, was sequestered in the spleen for months to consistently activate spleen memory CD3-CD19-Hyal-2+ Z cells to block pentylenetetrazol (PTZ)-induced seizures in mice, by preventing neuronal loss, reducing inflammatory microglia and astrocytes, and enhancing locomotion.Activated Z cells induced the expansion of MAP2+ and DAT+ (dopamine transporter) neurons and Nanog+/SOX2+ neural stem cells, and upregulated anti-inflammatory proteins and restored short-term memory loss in 3xTg-AD mice.By protein chip and gene expression profiling, Zfra-binding proteins MXD4, PPIA, and CHCHD4 were isolated.In vivo, inhibition of these proteins by specific IgG led to significant reduction in seizures and enhanced performance in the pole test.In summary, Zfra4-10 activated Z cells via the WWOX/PPIA/CHCHD4/MXD4 signaling to suppress seizures, block AD progression, and enhance locomotion in mice.