Premium
Control of hippocampal prothrombin kringle‐2 (pKr‐2) expression reduces neurotoxic symptoms in five familial Alzheimer's disease mice
Author(s) -
Kim Sehwan,
Moon Gyeong Joon,
Kim Hyung Jun,
Kim DoGeun,
Kim Jaekwang,
Nam Youngpyo,
Sharma Chanchal,
Leem Eunju,
Lee Shinrye,
Kim KyuSung,
Ha Chang Man,
McLean Catriona,
Jin Byung Kwan,
Shin WonHo,
Kim Dong Woon,
Oh YongSeok,
Hong ChangWon,
Kim Sang Ryong
Publication year - 2022
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15681
Subject(s) - hippocampal formation , neurodegeneration , protein kinase r , alzheimer's disease , medicine , endocrinology , thrombin , neuroscience , biology , pharmacology , kinase , microbiology and biotechnology , protein kinase a , platelet , disease , mitogen activated protein kinase kinase
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.