pKr-2 induces neurodegeneration via upregulation of microglial TLR4 in the hippocampus of AD brain

Sehwan Kim; Chanchal Sharma; Minsang Shin; Hyung-Jun Kim; Jaekwang Kim; Sang Ryong Kim

doi:10.1016/j.bbih.2023.100593

pKr-2 induces neurodegeneration via upregulation of microglial TLR4 in the hippocampus of AD brain

Brain Behav Immun Health. 2023 Jan 18:28:100593. doi: 10.1016/j.bbih.2023.100593. eCollection 2023 Mar.

Authors

Sehwan Kim^{1

2}, Chanchal Sharma^{1

3}, Minsang Shin⁴, Hyung-Jun Kim⁵, Jaekwang Kim⁵, Sang Ryong Kim^{1

2

3}

Affiliations

¹ School of Life Sciences, Kyungpook National University, Daegu, 41566, South Korea.
² Brain Science and Engineering Institute, Kyungpook National University, Daegu, 41944, South Korea.
³ BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, South Korea.
⁴ Department of Microbiology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
⁵ Dementia Research Group, Korea Brain Research Institute, Daegu, 41068, Republic of Korea.

Abstract

We recently demonstrated that prothrombin kringle-2 (pKr-2) derived from blood-brain barrier (BBB) disruption could induce hippocampal neurodegeneration and object recognition impairment through neurotoxic inflammatory responses in the five familial Alzheimer's disease mutation (5XFAD) mice. In the present study, we aimed to determine whether pKr-2 induces microglial activation by stimulating toll-like receptor 4 (TLR4) upregulation and examine whether this response contributes to pKr-2-induced neuroinflammatory damage in the hippocampi of mice models. We observed that inflammatory responses induced by pKr-2 administration in the hippocampi of wild-type mice were significantly abrogated in TLR4-deficient mice (TLR4^-/-), and caffeine supply or rivaroxaban treatment that inhibits the overexpression of hippocampal pKr-2 reduced TLR4 upregulation in 5XFAD mice, resulting in the inhibition of neuroinflammatory responses. Similar to the expression patterns of pKr-2, TLR4, and the TLR4 transcription factors, PU.1 and p-c-Jun, seen in the postmortem hippocampal tissues of Alzheimer's disease (AD) patients, our results additionally showed the influence of transcriptional regulation on TLR4 expression following pKr-2 expression in triggering the production of neurotoxic inflammatory mediators. Therefore, we conclude that pKr-2 may play a role in initiating upregulation of microglial TLR4, consequently inducing hippocampal neurodegeneration. Furthermore, the control of pKr-2-induced microglial TLR4 could be a useful therapeutic strategy against hippocampal neurodegeneration in AD.

Keywords: Alzheimer's disease; Hippocampus; Microglia; Neurodegeneration; Neuroinflammation; Prothrombin kringle-2; Toll-like receptor 4.