Inhibition of Drp1 Ameliorates Synaptic Depression, Aβ Deposition, and Cognitive Impairment in an Alzheimer's Disease Model

被引：239

作者：

Baek, Seung Hyun ^{[1
]}

Park, So Jung ^{[2
]}

Jeong, Jae In ^{[1
]}

Kim, Sung Hyun ^{[3
]}

Han, Jihoon ^{[1
]}

Kyung, Jae Won ^{[3
]}

Baik, Sang-Ha ^{[1
]}

Choi, Yuri ^{[1
]}

Choi, Bo Youn ^{[1
]}

Park, Jin Su ^{[1
,4
]}

Bahn, Gahee ^{[1
]}

Shin, Ji Hyun ^{[2
]}

Jo, Doo Sin ^{[2
]}

Lee, Joo-Yong ^{[5
]}

Jang, Choon-Gon ^{[1
]}

Arumugam, Thiruma V. ^{[1
,6
]}

Kim, Jongpil ^{[7
]}

Han, Jeung-Whan ^{[1
]}

Koh, Jae-Young ^{[5
]}

Cho, Dong-Hyung ^{[2
]}

Jo, Dong-Gyu ^{[1
,4
]}

机构：

[1] Sungkyunkwan Univ, Sch Pharm, Suwon 16419, South Korea

[2] Kyung Hee Univ, Grad Sch East West Med Sci, Yongin 17104, South Korea

[3] Kyung Hee Univ, Sch Med, Dept Physiol, Yongin 02447, South Korea

[4] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Suwon 06351, South Korea

[5] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Neurol, Ulsan 05505, South Korea

[6] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Physiol, Singapore 117593, Singapore

[7] Dongguk Univ, Dept Biomed Engn, Plus Team BK21, Seoul 100715, South Korea

来源：

JOURNAL OF NEUROSCIENCE | 2017年 / 37卷 / 20期

基金：

新加坡国家研究基金会;

关键词：

Alzheimer's; amyloid; Drp1; mitochondria; synaptic depression; ABNORMAL MITOCHONDRIAL DYNAMICS; AMYLOID-BETA; OXIDATIVE STRESS; SELECTIVE INHIBITOR; HUNTINGTONS-DISEASE; NEURONAL INJURY; S-NITROSYLATION; PROTEIN DRP1; MOUSE MODEL; FISSION;

D O I：

10.1523/JNEUROSCI.2385-16.2017

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-beta(A beta) in neurons and neuropathology and cognitive functions in A beta precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in A beta-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and A beta deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in A beta-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD.

引用

页码：5099 / 5110

页数：12

共 59 条

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