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Effect of Reserpine on the Behavioral Defects, Aβ-42 Deposition and NGF Metabolism in Tg2576 Transgenic Mouse Model for Alzheimer's Disease

알츠하이머질환 모델동물인 Tg2576마우스의 행동, Aβ-42 침적, 신경성장인자 대사에 미치는 reserpine의 영향

  • Go, Jun (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Choi, Sun Il (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Kim, Ji Eun (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Lee, Young Ju (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Kwak, Moon Hwa (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Koh, Eun Kyoung (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Song, Sung Hwa (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Sung, Ji Eun (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University) ;
  • Hwang, Dae Youn (Department of Biomaterials Science, College of Natural Resources and Life Science, Pusan National University)
  • 고준 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 최선일 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 김지은 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 이영주 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 곽문화 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 고은경 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 송성화 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 성지은 (부산대학교 생명자원과학대학 바이오소재과학과) ;
  • 황대연 (부산대학교 생명자원과학대학 바이오소재과학과)
  • Received : 2013.03.25
  • Accepted : 2013.06.17
  • Published : 2013.06.30

Abstract

Reserpine, an anti-hypertensive drug, is able to positively modulate several phenotypes associated with $A{\beta}$ toxicity in a Caenorhabditis elegans model of Alzheimer's disease (AD). We investigated into the therapeutic effects of reserpine on mammalian neurodegenerative disorders, and found that significant alteration of the key factors influencing AD was detected in Tg2576 mice after reserpine treatment for 30 days. The aggressive behavior of Tg2576 mice was significantly improved upon reserpine treatment, whereas their social contact was consistently maintained. Furthermore, the levels of $A{\beta}$-42 peptide in the hippocampus of the brain and blood serum were lower in the reserpine-treated group than in the vehicle-treated group. Among g-secretase components, the expression levels of PS-2, Pen-2, and APH-1 were slightly lower in reserpine-treated Tg2576 mice, although a significant change in nicastrin (NCT) expression was not detected. Furthermore, the serum level of nerve growth factor (NGF) increased in reserpine-treated Tg2576 mice compared with vehicle-treated mice. Among down-stream effectors of the NGF receptor TrkA signaling pathway, reserpine treatment induced elevation of TrkA phosphorylation and reduction of ERK phosphorylation. In addition, in the NGF receptor $p75^{NTR}$ signaling pathway, the expression levels of $p75^{NTR}$ and Bcl-2 were enhanced in reserpine-treated Tg2576 mice compared with vehicle-treated mice, whereas the expression level of RhoA declined. Overall, these results suggest that reserpine can help relieve AD pathogenesis in Tg2576 mice through downregulation of $A{\beta}$-42 deposition, alteration of ${\gamma}$-secretase components, and regulation of NGF metabolism.

Reserpine은 항고혈압제로서 알츠하이머질병의 증상을 나타내는 Caenorhabditis elegans에서 세포독성을 감소시켜 마비를 억제하고 수명을 연장시키는 것으로 알려져 있다. 본 연구에서는 이러한 reserpine의 효능을 포유동물에서 확인하기 위하여, 알츠하이머질병의 병리적 특성과 연관된 주요인자의 변화를 30일 동안 reserpine을 투여한 Tg2576 마우스에서 관찰하였다. 그 결과, 공격행동(aggressive behavior)은 vehicle 투여 그룹에 비하여 reserpine 투여 그룹에서 유의적으로 감소하였으나 사회적 접촉(social contact)은 유의적인 변화가 없었다. 뇌의 해마부분에서 알츠하이머질병의 원인 중 하나인 $A{\beta}$-42의 축적은 reserpine 투여 그룹에서 유의적으로 감소하였고, $A{\beta}$-42의 농도도 대조군에 비하여 reserpine 투여 그룹에서 감소하였다. 더불어, ${\gamma}$-secretase의 구성단백질 중에서 PS-2, Pen-2, APH-1의 발현은 대조군에 비하여 reserpine 투여군에서 유의적으로 감소하였으나 NCT 발현은 변화가 없었다. 혈청에서 NGF의 농도는 Tg2576 마우스에서 감소하였다가 reserpine 투여한 그룹에서 유의적으로 증가하였으며, high affinity receptor의 신호전달과정에 포함된 단백질 중에서 reserpine 투여 그룹은 TrkA의 인산화가 증가하고 ERK 인산화는 감소되었다. 한편 low affinity receptor의 신호전달과정에서, $p75^{NTR}$과 Bcl-2의 발현은 vehicle 그룹에 비하여 reserpine 투여 그룹에서 유의적으로 발현이 증가하였으나 RhoA의 발현은 reserpine 투여 그룹에서 감소하였다. 따라서 이러한 결과는 reserpine은 포유동물 치매모델인 Tg2576 마우스에서 행동학적 변화, $A{\beta}$-42의 축적, NGF의 농도, NGF신호전달의 변화 등을 유도하며, 향후 치매치료제로서 가능성을 제시하고 있다.

Keywords

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