Zfra suppresses seizure and progression of Alzheimer's disease via activated Z lymphocytes

Abstract

As a tumor suppressor, WWOX is a recently defined risk factor for Alzheimer's disease (AD). WWOX limits AD progression due, in part, to its suppression of tau tangle formation by direct binding of tau and tau-phosphorylating enzymes. Deficiency of WWOX leads to severe neural diseases such as epileptic encephalopathy, microcephaly, and early death in newborns. During AD progression, pS14-WWOX and aggregated TRAPPC6AΔ, TIAF1, SH3GLB2, tau and amyloid beta are accumulated in the auditory cortex and hippocampal CA1, CA3, or DG areas of the brains of triple transgenic (3xTg) mice and heterozygous Wwox mice. Here, we determined that suppression of pS14-WWOX by a zinc finger-like peptide Zfra4-10 leads to clearup of tau tangles and amyloid plaques, reduced activation of inflammatory microglia and astrocytes, downregulated epilepsy-related REST protein expression, and restored memory loss in 3xTg mice and heterozygous Wwox mice. Notably, the Zfra action is due in part to its activated Hyal-2+ spleen Z lymphocytes. When purified activated Z cells were transferred to recipient 3xTg mice, these mice strongly resisted Pentylenetetrazole (PTZ)-induced seizure. Whether Z cells block AD progression are being determined in our laboratory. There are 2% Z cells in the brain. Transfer of brain Z cells to recipient mice also confers resistance to PTZ-induced seizure. Taken together, both Zfra peptide and Z cells are expected to be of great therapeutic potential for AD patients or seizure-stricken WWOX-deficient newborns.