Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 20, Pages 5099-5110Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2385-16.2017
Keywords
Alzheimer's; amyloid; Drp1; mitochondria; synaptic depression
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Funding
- Korean Health 21 RD Project [HI14C2539, HI16C1176]
- Ministry of Health and Welfare, Republic of Korea [A120196]
- National Research Foundation of Korea (NRF)
- Ministry of Education, Science and Technology, Republic of Korea [2012R1A5A2A28671860, 2015R1A2A1A01003530]
- National Research Foundation of Korea [2015R1A2A1A01003530] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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