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Dying Neurons Conduct Repair Processes in the Injured Brain through Osteopontin Expression in Cooperation with Infiltrated Blood Monocytes
- Subtitle
- Impaired by LRRK2 G2019S Mutation
- Author(s)
- AN JIAWEI
- Advisor
- Eun-Hye Joe
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2022-02
- Language
- eng
- Keyword
- LRRK2 G2019S; brain repair; exosome; monocyte; osteopontin
- Alternative Abstract
- The brain has an intrinsic capacity to repair injury, but its specific mechanisms are largely unknown. In the first part of the study, I found that, in wild type mice, despite their incipient death, damaged neurons play a key role in the repair of the damaged brain lesion with the help of monocytes infiltrated from blood. Monocytes phagocytosed damaged and/or dying neurons expressing osteopontin (OPN), then, possibly activated their inflammasome pathway, resulting in pyroptosis. During this process, monocytes released CD63-positive exosome-like vesicles containing OPN. Importantly, following the released exosome-like vesicles, the processes of the neuron and astrocyte were elongated toward the injury core. In addition, the exosomes prepared from the injured brain contained OPN and enhanced neurite outgrowth of cultured neurons in an OPNdependent manner. Thus, the results prove the concept that, in wild type (WT) mice, neurons in the injured brain that are destined to die, perceive the stressful condition and begin the regeneration processes through induction of OPN, ultimately executing the repair process with the help of monocytes recruited from the circulation. In the second part of the study, I examined the roles of brain cells for the repair of the injured brain in an animal model of Parkinson’s disease, LRRK2 G2019S mutant mice. LRRK2 G2019S mutation leads to a reduction in neuron process length and complexity in vitro. I found that in vivo LRRK2 G2019S brains also showed impaired regeneration capacities after injury. Notably, the number of regeneration-related OPN-positive exosomal particles was reduced, consequentially the OPN-related cellular behaviors were also attenuated in the injured LRRK2 G2019S brains. Inflammasome activation and pyroptosis of the infiltrated monocytes were clearly associated with the release of OPN-positive exosomal particles in the injured brains. Monocyte infiltration in the LRRK2 G2019S brains was almost identical to that in the WT brains. In LRRK2 G2019S mice, however, inflammasome activation and pyroptosis of the monocytes were reduced in vivo and in vitro. Moreover, exosomes containing OPN or recombinant OPN could rescue defects of neurite outgrowth in LRRK2 G2019S neurons. Thus, these findings clearly prove that reduction of OPN-containing exosomes results in the defect of repairing capacities in injured LRRK2 G2019S brains, which could be caused by attenuation of inflammasome activation and subsequent pyroptosis in the infiltrated monocytes.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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