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

Abstract

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.

Alzheimer’s Disease: Molecular Hallmarks and Yeast Models

“…Importantly, mdivi-1 treatment markedly decreased extracellular amyloid deposition, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters, supporting the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and AD-related pathological and cognitive impairments in vivo [72,73]. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1p (responsible for mitochondrial fragmentation) in the pathogenesis of AD and that inhibiting excessive Drp1p-mediated mitochondrial fission may be a new efficient therapeutic strategy for AD.…”

“…Treatment by mdivi-1, a mitochondrial fission inhibitor, rescued the mitochondrial fragmentation and distribution deficits and improve mitochondrial function in the Aβ-treated [72] and CRND8 [73] neurons both in vitro and in vivo. Importantly, mdivi-1 treatment markedly decreased extracellular amyloid deposition, prevented the development of cognitive deficits in Y-maze test and improved synaptic parameters, supporting the notion that abnormal mitochondrial dynamics plays an early and causal role in mitochondrial dysfunction and AD-related pathological and cognitive impairments in vivo [72,73].…”

“…Excessive mitochondrial fission (fragmentation) is a prominent early event, contributing to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of AD [40,71,72]. Moreover, mitochondria fragmentation, like a mitochondrial bioenergetic deficit, is an early feature preceding AD pathology in APP transgenic animal models [40] and mouse model CRND8 [73].…”

Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer’s Disease

“…Further, our in vitro studies revealed that Mdivi1 is protective against Aβ-induced excessive mitochondrial fragmentation and mitochondrial dysfunction in AD neurons [47]. Several recent mouse model studies of AD, also revealed that Mdivi1 is protective against Aβ-induced synaptic and mitochondrial toxicities, particularly Mdivi1 reduces excessive mitochondrial fragmentation [53–54]. Very little is known about synergistic protective effects of SS31 and Mdivi1 in AD neurons.…”

“…Several recent studies also reported that mitochondria-targeted molecules and mitochondrial division inhibitors reduce Aβ levels and mitochondrial and synaptic toxicities in AD neurons [47,53,54]. However, there are no published reports that investigated using combined treatments of mitochondria-targeted molecules and mitochondrial division inhibitors.…”