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

Neurobiol Aging. 2021 Feb;98:63-77. doi: 10.1016/j.neurobiolaging.2020.09.018. Epub 2020 Oct 16.

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.

Keywords: Alzheimer's disease; Amyloid beta; Mitochondrial F1Fo ATP synthase; Oligomycin-sensitivity-conferring protein; Synaptic injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / psychology
  • Alzheimer Disease / therapy
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Disease Models, Animal
  • Gene Expression
  • Memory
  • Mice, Transgenic
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondrial Dynamics / genetics
  • Mitochondrial Proton-Translocating ATPases / genetics
  • Mitochondrial Proton-Translocating ATPases / metabolism
  • Mitochondrial Proton-Translocating ATPases / physiology*
  • Molecular Targeted Therapy
  • Neurons / metabolism
  • Spatial Learning
  • Synaptic Transmission / genetics*

Substances

  • Amyloid beta-Peptides
  • F1F0-ATP synthase
  • Mitochondrial Proton-Translocating ATPases
  • oligomycin sensitivity-conferring protein