Control of hippocampal prothrombin kringle-2 (pKr-2) expression reduces neurotoxic symptoms in five familial Alzheimer's disease mice

Sehwan Kim, Gyeong Joon Moon, Hyung Jun Kim, Do Geun Kim, Jaekwang Kim, Youngpyo Nam, Chanchal Sharma, Eunju Leem, Shinrye Lee, Kyu Sung Kim, Chang Man Ha, Catriona McLean, Byung Kwan Jin, Won Ho Shin, Dong Woon Kim, Yong Seok Oh, Chang Won Hong, Sang Ryong Kim

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background and Purpose: There is a scarcity of information regarding the role of prothrombin kringle-2 (pKr-2), which can be generated by active thrombin, in hippocampal neurodegeneration and Alzheimer's disease (AD). Experimental Approach: To assess the role of pKr-2 in association with the neurotoxic symptoms of AD, we determined pKr-2 protein levels in post-mortem hippocampal tissues of patients with AD and the hippocampi of five familial AD (5XFAD) mice compared with those of age-matched controls and wild-type (WT) mice, respectively. In addition, we investigated whether the hippocampal neurodegeneration and object memory impairments shown in 5XFAD mice were mediated by changes to pKr-2 up-regulation. Key Results: Our results demonstrated that pKr-2 was up-regulated in the hippocampi of patients with AD and 5XFAD mice, but was not associated with amyloid-β aggregation in 5XFAD mice. The up-regulation of pKr-2 expression was inhibited by preservation of the blood–brain barrier (BBB) via addition of caffeine to their water supply or by treatment with rivaroxaban, an inhibitor of factor Xa that is associated with thrombin production. Moreover, the prevention of up-regulation of pKr-2 expression reduced neurotoxic symptoms, such as hippocampal neurodegeneration and object recognition decline due to neurotoxic inflammatory responses in 5XFAD mice. Conclusion and Implications: We identified a novel pathological mechanism of AD mediated by abnormal accumulation of pKr-2, which functions as an important pathogenic factor in the adult brain via blood brain barrier (BBB) breakdown. Thus, pKr-2 represents a novel target for AD therapeutic strategies and those for related conditions.

Original languageEnglish
Pages (from-to)998-1016
Number of pages19
JournalBritish Journal of Pharmacology
Volume179
Issue number5
DOIs
StatePublished - Mar 2022

Keywords

  • Alzheimer's disease
  • blood–brain barrier
  • hippocampus
  • microglia
  • prothrombin kringle-2

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