A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam

J Alzheimers Dis. 2016;50(1):201-15. doi: 10.3233/JAD-150687.

Abstract

Aberrant neuronal network activity associated with neuronal hyperexcitability seems to be an important cause of cognitive decline in aging and Alzheimer's disease (AD). Out of many antiepileptics, only levetiracetam improved cognitive dysfunction in AD patients and AD animal models by reducing hyperexcitability. As impaired inhibitory interneuronal function, rather than overactive neurons, seems to be the underlying cause, improving impaired neuronal function rather than quieting overactive neurons might be relevant in explaining the lack of activity of the other antiepileptics. Interestingly, improvement of cognitive deficits by levetiracetam caused by small levels of soluble Aβ was accompanied by improvement of synaptic function and plasticity. As the negative effects of Aβ on synaptic plasticity strongly correlate with mitochondrial dysfunction, wehypothesized that the effect of levetiracetam on synaptic activity might be raised by an improved mitochondrial function. Accordingly, we investigated possible effects of levetiracetam on neuronal deficits associated with mitochondrial dysfunction linked to aging and AD. Levetiracetam improved several aspects of mitochondrial dysfunction including alterations of fission and fusion balance in a cell model for aging and early late-onset AD. We demonstrate for the first time, using immunohistochemistry and proteomics, that the synaptic vesicle protein 2A (SV2a), the molecular target of levetiracetam, is expressed in mitochondria. In addition, levetiracetam shows significant effect on the opening of the mitochondrial permeability transition pore. Importantly, the effects of levetiracetam were significantly abolished when SV2a was knockdown using siRNA. In conclusion, interfering with the SV2a protein at the mitochondrial level and thereby improving mitochondrial function might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD.

Keywords: Aging; Alzheimer’s disease; amyloid-β; levetiracetam; mitochondrial dynamics; mitochondrial function; mitochondrial permeability transition; synaptic vesicle protein 2A (SV2a).

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aging / pathology*
  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / pathology
  • Animals
  • Brain / ultrastructure
  • Cell Line
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology
  • Female
  • GAP-43 Protein / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Levetiracetam
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondrial Membrane Transport Proteins / drug effects
  • Mitochondrial Permeability Transition Pore
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nitroprusside / pharmacology
  • Nootropic Agents / therapeutic use*
  • Piracetam / analogs & derivatives*
  • Piracetam / therapeutic use
  • Proteomics
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats

Substances

  • GAP-43 Protein
  • Membrane Glycoproteins
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Nerve Tissue Proteins
  • Nootropic Agents
  • RNA, Small Interfering
  • Sv2a protein, mouse
  • Nitroprusside
  • Levetiracetam
  • Adenosine Triphosphate
  • Piracetam