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

Apr 23, 2017The Journal of neuroscience : the official journal of the Society for Neuroscience

Blocking Drp1 reduces synapse loss, amyloid buildup, and memory problems in an Alzheimer's model

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Abstract

Inhibition of dynamin-related protein 1 (Drp1) significantly improves learning and memory in Alzheimer's disease mice.

Excessive mitochondrial fission is linked to mitochondrial dysfunction, synaptic failure, and neuronal cell death in Alzheimer's disease.
Drp1 inhibition reduces mitochondrial fragmentation, restores mitochondrial membrane potential, and decreases reactive oxygen species production in Aβ-treated neurons.
In an Alzheimer's disease mouse model, Drp1 inhibition prevents lipid peroxidation and reduces the expression of BACE1 and amyloid-β deposition in the brain.
Memory deficits in Alzheimer's disease mice were alleviated by the inhibition of Drp1, suggesting its role in cognitive decline.
These findings indicate that targeting Drp1 may represent a potential therapeutic strategy for Alzheimer's disease.

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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-β (Aβ) in neurons and neuropathology and cognitive functions in Aβ 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 Aβ-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and Aβ deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in Aβ-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.Mitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-β (Aβ)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and Aβ deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD. SIGNIFICANCE STATEMENT

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

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