title: A Mitochondrial Role of SV2a Protein in Aging and Alzheimer's Disease: Studies with Levetiracetam.
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.
authors.affiliation: Department of Pharmacology, University of Frankfurt/M, Biocenter, Frankfurt/M, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Stockburger
authors.affiliation: Department of Pharmacology, University of Frankfurt/M, Biocenter, Frankfurt/M, Germany.
authors.forename: Davide
authors.initials: D
authors.lastname: Miano
authors.affiliation: Institute of Pharmaceutical Chemistry, Cluster of Excellence "Macromolecular Complexes", Goethe-University Frankfurt, Frankfurt/M, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Baeumlisberger
authors.affiliation: Department of Pharmacology, University of Frankfurt/M, Biocenter, Frankfurt/M, Germany.
authors.forename: Thea
authors.initials: T
authors.lastname: Pallas
authors.affiliation: Thermo Fisher Scientific, Bremen, Germany.
authors.forename: Tabiwang N
authors.initials: TN
authors.lastname: Arrey
authors.affiliation: Institute of Pharmaceutical Chemistry, Cluster of Excellence "Macromolecular Complexes", Goethe-University Frankfurt, Frankfurt/M, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Karas
authors.affiliation: Molecular and Clinical Pharmacy, Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen/Nuremberg, Erlangen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Friedland
authors.affiliation: Department of Pharmacology, University of Frankfurt/M, Biocenter, Frankfurt/M, Germany.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Müller
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000648:ultrastructure; D002460:Cell Line; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D018697:Nootropic Agents / Q000627:therapeutic use*; D010889:Piracetam / Q000031:analogs & derivatives* / Q000627:therapeutic use; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats
chemical_list: D019922:GAP-43 Protein; D008562:Membrane Glycoproteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D034741:RNA, Small Interfering; C489614:Sv2a protein, mouse; D009599:Nitroprusside; D000077287:Levetiracetam; D000255:Adenosine Triphosphate; D010889:Piracetam
keywords: Aging; Alzheimer’s disease; amyloid-β; levetiracetam; mitochondrial dynamics; mitochondrial function; mitochondrial permeability transition; synaptic vesicle protein 2A (SV2a)