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

Stockburger, Carola; Miano, Davide; Baeumlisberger, Marion; Pallas, Thea; Arrey, Tabiwang N.; Karas, Michael; Friedland, Kristina; Müller, Wernér E.G.

doi:10.3233/jad-150687

Cited by 52 publications

(63 citation statements)

References 60 publications

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“…These vitamins are α-lipoic acid, vitamin E, vitamin C, N-acetylcysteine (NAC) and inducers of the heme oxygenase, which are responsible for reduced ROS production [107]. Further, treatment with antiepileptic drug, Levetiracetam has been found to be associated with ameliorating numerous aspects of mitochondrial dysfunction such as alterations of fission-fusion balance in a cell model for aging and early/late-onset AD [108]. Likewise, another biomolecule Icariin has also benefitted against mitochondrial fragmentation associated with Aβ 1-42 accumulation in 3 × Tg-AD neurons [109].…”

Section: Biomolecules Mediated Therapy For Altered Mitochondrial Dynamentioning

confidence: 98%

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

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Section: Biomolecules Mediated Therapy For Altered Mitochondrial Dynamentioning

confidence: 98%

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Mitochondria dysfunction is another parameter that can take part in AD development (Swerdlow, 2012). Interestingly, SV2A was also localized in mitochondria of aging and late-onset AD cell models (Stockburger et al, 2016). In the same model, positive effects of LEV treatment on the mitochondrial fission and fusion balance were abolished if SV2A expression was invalidated by siRNA.…”

Section: Sv2a In the Pathophysiology Of Neurological Diseasesmentioning

confidence: 99%

Puzzling Out Synaptic Vesicle 2 Family Members Functions

Bartholomé

Ackerveken

Gil

et al. 2017

Front. Mol. Neurosci.

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Synaptic vesicle proteins 2 (SV2) were discovered in the early 80s, but the clear demonstration that SV2A is the target of efficacious anti-epileptic drugs from the racetam family stimulated efforts to improve understanding of its role in the brain. Many functions have been suggested for SV2 proteins including ions or neurotransmitters transport or priming of SVs. Moreover, several recent studies highlighted the link between SV2 and different neuronal disorders such as epilepsy, Schizophrenia (SCZ), Alzheimer’s or Parkinson’s disease. In this review article, we will summarize our present knowledge on SV2A function(s) and its potential role(s) in the pathophysiology of various brain disorders.

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“…Levetiracetam treatment of APP transgenic mice has similarly been reported to improve cognitive function, whereas other anti-seizure agents fail to do so [63]. In a cell model for aging and early late-onset AD, levetiracetam improved several aspects of mitochondrial dysfunction, which were abolished when SV2A was knocked down by small interfering RNA (siRNA), indicating that interfering with SV2A at the mitochondrial level, and thereby improving mitochondrial function, might represent an additional therapeutic effect of levetiracetam to improve symptoms of late-onset AD [64]. Taken together, these data support a potential role of SV2A in AD and have stimulated an interest in exploring the therapeutic potential of levetiracetam as a novel therapeutic approach for AD treatment.…”

Section: The Role Of Sv2a In Modulating Neuronal Excitability In the mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

Löscher¹,

et al. 2016

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The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology. While the functional consequences of SV2A ligand binding are not fully elucidated, studies suggest that subsequent SV2A conformational changes may contribute to seizure protection. Conversely, the recently discovered negative SV2A modulators, such as UCB0255, counteract the anti-seizure effect of levetiracetam and display procognitive properties in preclinical models. More broadly, dysfunction of SV2A may also be involved in Alzheimer’s disease and other types of cognitive impairment, suggesting potential novel therapies for levetiracetam and its congeners. Furthermore, emerging data indicate that there may be important roles for two other SV2 isoforms (SV2B and SV2C) in the pathogenesis of epilepsy, as well as other neurodegenerative diseases. Utilization of recently developed SV2A positron emission tomography ligands will strengthen and reinforce the pharmacological evidence that SV2A is a druggable target, and will provide a better understanding of its role in epilepsy and other neurological diseases, aiding in further defining the full therapeutic potential of SV2A modulation.

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

Cited by 52 publications

References 60 publications

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Puzzling Out Synaptic Vesicle 2 Family Members Functions

Synaptic Vesicle Glycoprotein 2A Ligands in the Treatment of Epilepsy and Beyond

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