Zfra and its activated Z cell suppress traumatic brain injury to Alzheimer's disease transition

As a risk factor for Alzheimer's disease(AD), WW domain‐containing oxidoreductase (WWOX) becomes phosphorylated at S14 in the lesions of AD hippocampus and cortex. It appears that the severity of AD progression is associated with pS14‐WWOX accumulation. Suppression of WWOX phosphorylation at S14 and clearance of tau and amyloid beta aggregation by a 7‐amino‐acid zinc finger like peptide Zfra4‐10 leads to restoration of memory loss in 10‐month‐old triple transgenic mice for AD (3xTg). Here, we test the hypothesis that transition of acute phase traumatic brain injury (TBI) to AD‐like symptoms in the chronic phase correlates with a shift of pY33 to pS14 in WWOX. When BALB/c mice were subjected to TBI, these mice exhibited rapid increases in the accumulation of aggregates of amyloid beta, alpha‐synuclein and neurofibrillary tangles (NFT), along with increases in the proapoptotic pY33‐WWOX. Zfra significantly cleared up the protein aggregates. A novel estrogen receptor‐binding protein ankyrin repeat domain 40 (ANR40) was isolated, and its phosphorylation at S154 identified. TBI upregulated ANR40 without S154 phosphorylation. In contrast, Zfra upregulated pS154‐ANR40 during the acute phase of TBI followed by reduction in chronic phase, suggesting that pS154‐ANR40 is neuroprotective. Additionally, Zfra‐activated spleen Hyal‐2+ Z cells are potent in blocking Pentylenetetrazole (PTZ)‐mediated seizure in 3xTg mice. When activated Z cells were transferred to TBI‐treated mice, their short‐term memory during novel objective test recovered significantly. Together, transition of TBI to AD‐like symptom with age in mice involves pY33‐WWOX disappearance and pS14‐WWOX accumulation. Both Zfra peptide and Z cells are of therapeutic value in TBI treatment.