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A potential role of Zfra in mitigating traumatic brain injury transition to Alzheimer’s disease‐like symptom in mice
Author(s) -
Liu Tsung-Yun,
Chang Nan-Shan
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03443
Subject(s) - hippocampus , traumatic brain injury , neurodegeneration , morris water navigation task , medicine , neuroscience , downregulation and upregulation , genetically modified mouse , psychology , endocrinology , transgene , disease , biology , psychiatry , biochemistry , gene
Most recently, tumor suppressor WWOX is defined as a risk factor for Alzheimer’s disease(AD). Previously, we determined that accumulation of pS14‐WWOX in the brain hippocampus and cortex correlates with the occurrence of AD and probably other neurodegeneration. Zinc finger‐like protein that regulates apoptosis (Zfra) suppresses pS14‐WWOX accumulation and restores memory loss in triple transgenic mice (3xTg) for AD. During the acute phase traumatic brain injury (TBI), overly expressed WWOX becomes phosphorylated at Tyr33 and is accumulated in the nuclei to cause neuronal death in the impacted areas. We determined that in the novel object recognition tests, mice surviving from TBI (2.8 to 3.3 Newtonian force) significantly spent less exploring time on new objects in both long‐term and short‐term memory tests post TBI for 18 weeks, indicating the occurrence of damage in long‐ and short‐term memory. Further, control and TBI mice were subjected to Morris water maze tests post TBI for 10 weeks to determine the hippocampus‐dependent, spatial memory. Both groups showed a time‐dependent decrease in escape latency, indicating that mild TBI didn’t affect the learning capabilities. BALB/c mice received Zfra4‐10 peptide via tail vein injections prior to TBI (1.7 Newtonian force). Two weeks later, these treated mice significantly spent more time on probing the new object in the short‐term memory task compared to control mice, suggesting that Zfra peptide prevents TBI‐induced memory loss. Interestingly, by immunohistochemistry, significant upregulation of tau phosphorylation at T181 and amyloid beta aggregates was shown rapidly in death‐inducing impact in BALB/c mice (3.5 Newton), and that Zfra significantly prevented the upregulation (~20 to 33%). Together, our observations suggest the transition of TBI to AD‐like symptom in mice are likely to occur, and that Zfra4‐10 peptide prevents the transition. Support or Funding Information Ministry of Science & Technology, Taiwan, National Health Research Institute, Taiwan, Department of Defense, USA