Modulation of OSCP mitigates mitochondrial and synaptic deficits in a mouse model of Alzheimer's pathology

Esha Gauba,Shaomei Sui,Jing Tian,Christopher Driskill,Kun Jia,Chunxiao Yu,Tripta Rughwani,Qi Wang,Sven Kroener,Lan Guo,Heng Du

doi:10.1016/j.neurobiolaging.2020.09.018

Esha Gauba, Shaomei Sui + Show 9 more

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https://doi.org/10.1016/j.neurobiolaging.2020.09.018

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Abstract

Synaptic failure underlies cognitive impairment in Alzheimer's disease (AD). Cumulative evidence suggests a strong link between mitochondrial dysfunction and synaptic deficits in AD. We previously found that oligomycin-sensitivity-conferring protein (OSCP) dysfunction produces pronounced neuronal mitochondrial defects in AD brains and a mouse model of AD pathology (5xFAD mice). Here, we prevented OSCP dysfunction by overexpressing OSCP in 5xFAD mouse neurons in vivo (Thy-1 OSCP/5xFAD mice). This approach protected OSCP expression and reduced interaction of amyloid-beta (Aβ) with membrane-bound OSCP. OSCP overexpression also alleviated F1Fo ATP synthase deregulation and preserved mitochondrial function. Moreover, OSCP modulation conferred resistance to Aβ-mediated defects in axonal mitochondrial dynamics and motility. Consistent with preserved neuronal mitochondrial function, OSCP overexpression ameliorated synaptic injury in 5xFAD mice as demonstrated by preserved synaptic density, reduced complement-dependent synapse elimination, and improved synaptic transmission, leading to preserved spatial learning and memory. Taken together, our findings show the consequences of OSCP dysfunction in the development of synaptic stress in AD-related conditions and implicate OSCP modulation as a potential therapeutic strategy.

Highlights

Oligomycin-sensitivity conferring protein (OSCP) is a critical subunit of mitochondrial F1Fo ATP synthase
These age ranges were selected based on our previous observations of OSCP changes, mitochondrial dysfunction, synaptic injury, and cognitive impairment in 5xFAD mice [12, 13, 19]
To determine whether OSCP overexpression affects the expression of other major subunits of F1Fo ATP synthase, we further examined the expression of α, β, γ, a, b, and c subunits

Summary

Introduction

Oligomycin-sensitivity conferring protein (OSCP) is a critical subunit of mitochondrial F1Fo ATP synthase. Previous observations of brain hypometabolism, oxidative damages, and energy deficiency support the mitochondrial cascade hypothesis of AD [5,6,7] It remains unclear whether mitochondrial dysfunction is a primary cause of AD, cumulative evidence supports a model in which mitochondrial defects confer susceptibility to Aβ-induced synaptotoxicity and neuronal stress, leading to irreversible damages and cognitive impairment [8]. For this reason, mitochondrial dysfunctions that contribute to AD-related neuronal perturbations might provide novel therapeutic targets to prevent neurodegenerative processes that stem from Aβ toxicity

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