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  • [Theranostics.] Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer's disease 선조체 MeCP2의 기능장애는 알츠하이머병 마우스 모델에서 인지 저하와

    서울대, KIST / 이상준, 김혜선*, 임혜인*

  • 출처
    Theranostics.
  • 등재일
    2022 Jan 1
  • 저널이슈번호
    12(3):1404-1418. doi: 10.7150/thno.68439. eCollection 2022.
  • 내용

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    Abstract
    Rationale: Cerebral Methyl-CpG binding Protein 2 (MeCP2) is involved in several psychiatric disorders that are concomitant with cognitive dysfunction. However, the regulatory function of striatal MeCP2 and its association with Alzheimer's disease (AD) has been largely neglected due to the absence of amyloid plaque accumulation in the striatal region until the later stages of AD progression. Considerable evidence indicates that neuropsychiatric symptoms related to cognitive decline are involved with striatal dysfunction. To this respect, we investigated the epigenetic function of striatal MeCP2 paralleling the pathogenesis of AD. Methods: We investigated the brain from amyloid precursor protein (APP)/presenilin1 (PS1) transgenic mice and postmortem brain samples from normal subjects and AD patients. The molecular changes in the brain, particularly in the striatal regions, were analyzed with thioflavin S staining, immunohistochemistry, immunoblotting, and MeCP2 chromatin immunoprecipitation sequencing (ChIP-seq). The cognitive function of APP/PS1 mice was assessed via three behavioral tests: 3-chamber test (3CT), Y-maze test (YMT), and passive avoidance test (PA). A multi-electrode array (MEA) was performed to analyze the neuronal activity of the striatum in APP/PS1 mice. Results: Striatal MeCP2 expression was increased in the younger (6 months) and older (10 months) ages of APP/PS1 mice, and the genome-wide occupancy of MeCP2 in the younger APP/PS1 showed dysregulated binding patterns in the striatum. Additionally, we confirmed that APP/PS1 mice showed behavioral deficits in multiple cognitive behaviors. Notably, defective cognitive phenotypes and abnormal neuronal activity in old APP/PS1 mice were rescued through the knock-down of striatal MeCP2. Conclusion: We found that the MeCP2-mediated dysregulation of the epigenome in the striatum is linked to the defects in cognitive behavior and neuronal activity in the AD animal model, and that this alteration is initiated even in the very early stages of AD pathogenesis. Together, our data indicates that MeCP2 may be a potential target for the diagnosis and treatment of AD at asymptomatic and symptomatic stages.

     

     

    Affiliations

    Sangjoon Lee  1   2   3 , Tae Kyoo Kim  1 , Ji Eun Choi  1   4 , Yunjung Choi  1   2 , Minsu You  1 , Jeewon Ryu  1 , Yoo Lim Chun  1 , Suji Ham  1 , Seung Jae Hyeon  3 , Hoon Ryu  1   3 , Hye-Sun Kim  2   5 , Heh-In Im  1   3   6
    1 Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
    2 Department of Pharmacology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.
    3 Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.
    4 Department of Biochemistry, Hanyang University College of Medicine, Seoul 04763, Korea.
    5 Seoul National University College of Medicine, Bundang Hospital, Sungnam 13620, Korea.
    6 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea.

  • 키워드
    Alzheimer`s disease; MeCP2; cognitive dysfunctions; epigenetic regulation; striatum.
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