Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease

Cassano, Tommaso; Serviddio, Gaetano; Gaetani, Silvana; Romano, Adele; Dipasquale, Pasqua; Cianci, Silvia; Bellanti, Francesco; Laconca, Leonardo; Romano, Antonino Davide; Padalino, Iolanda; LaFerla, Frank M.; Nicoletti, Ferdinando; Cuomo, V.; Vendemiale, Gianluigi

doi:10.1016/j.neurobiolaging.2011.09.021

Cited by 86 publications

(77 citation statements)

References 36 publications

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“…The association of SV2A with AD has not been described, but some disorientation in AD is associated with epileptiform activity and might be prevented with antiepileptic drugs (62). In contrast, VGLUT1, the vesicular glutamate transporter in neurons, has been found to be differentially expressed in different AD mouse models (63,64). The observation that FE65 is associated with synaptic plasticity (65) might in part be due to the interaction of FE65 with SV2A and VGLUT1.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

Nensa

Neumann

Schrötter

et al. 2014

Molecular & Cellular Proteomics

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ller ‡ §ʈʈ FE65 is a cytosolic adapter protein and an important binding partner of amyloid precursor protein. Dependent on Thr668 phosphorylation in amyloid precursor protein, which influences amyloidogenic amyloid precursor protein processing, FE65 undergoes nuclear translocation, thereby transmitting a signal from the cell membrane to the nucleus. As this translocation may be relevant in Alzheimer disease, and as FE65 consists of three proteinprotein interaction domains able to bind and affect a variety of other proteins and downstream signaling pathways, the identification of the FE65 interactome is of central interest in Alzheimer disease research. In this study, we identified 121 proteins as new potential FE65 interacting proteins in a pulldown/mass spectrometry approach using human post-mortem brain samples as protein pools for recombinantly expressed FE65. Co-immunoprecipitation assays further validated the interaction of FE65 with the candidates SV2A and SERCA2. In parallel, we investigated the whole cell proteome of primary hippocampal neurons from FE65/FE65L1 double knockout mice. Notably, the validated FE65 binding proteins were also found to be differentially abundant in neurons derived from the FE65 knockout mice relative to wild-type control neurons. SERCA2 is an important player in cellular calcium homeostasis, which was found to be up-regulated in double knockout neurons. Indeed, knock-down of FE65 in HEK293T cells also evoked an elevated sensitivity to thapsigargin, a stressor specifically targeting the activity of SERCA2. Thus, our results suggest that FE65 is involved in the regulation of intracellular calcium homeostasis. Whereas transfection of FE65 alone caused a typical dotlike phenotype in the nucleus, co-transfection of SV2A significantly reduced the percentage of FE65 dot-positive cells, pointing to a possible role for SV2A in the modulation of FE65 intracellular targeting. Given that SV2A has a signaling function at the presynapse, its effect on FE65 intracellular localization suggests that the SV2A/FE65 interaction might play a role in synaptic signal transduction. Molecular

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Section: Discussionmentioning

confidence: 99%

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

Nensa

Neumann

Schrötter

et al. 2014

Molecular & Cellular Proteomics

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“…23,24) On the other hand, dysfunction in neurotransmission mediated by the inhibitory neurotransmitter GABA is related to the onset and development of several neurological disorders including epilepsy and insomnia. 25,26) The high-affinity transporters for glutamic acid and GABA are EAAT and GAT, respectively, but the low-affinity transporters are unclear.…”

Section: Physiological Roles Of Organic Cation Transporters In Neuronsmentioning

confidence: 99%

“…In brain neurons, on the other hand, the OCTN1-mediated uptake of ERGO could play a protective role against the oxidative stress related to the development of various neurological disorders, including Alzheimer's, Parkinson's, and Huntington's diseases. 23,46) In addition, OCTN1 is functionally expressed in neural stem cells as well as neurons, and the OCTN1-mediated uptake of ERGO promotes differentiation of neural stem cells into neurons. 35) Taken together, the induction of OCTN1 and/or the ingestion of ERGO are conceivable as treatments for neurological disorders associated with OCTN1.…”

Section: )mentioning

confidence: 99%

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

Nakamichi

Kato

2017

Biological & Pharmaceutical Bulletin

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Dysfunction in neurotransmission mediated by neurotransmitters causes various neurological disorders.Therefore, receptors and reuptake transporters of neurotransmitters have been focused on as a therapeutic target in neurological disorders. These membrane proteins have high affinity for a specific neurotransmitter and are highly expressed on synaptic membranes. In contrast, xenobiotic transporters have relatively lower affinity for neurotransmitters but widely recognize various organic cations and/or anions and are also expressed in brain neurons. However, it has been largely unknown why such xenobiotic transporters are expressed in neurons that play a key role in signal transduction. We have therefore attempted to clarify the physiological roles of one such xenobiotic organic cation transporter (OCT) in neural cells with the aim of obtaining new insight into the treatment of neurological disorders. Carnitine/organic cation transporter OCTN1/SLC22A4 is functionally expressed in neurons and neural stem cells. In particular, OCTN1 is expressed at much higher levels compared with other OCTs in neural stem cells and positively regulates their differentiation into neurons. OCTN1 accepts the naturally occurring food-derived antioxidant ergothioneine (ERGO) as a good in vivo substrate. Because ERGO is highly distributed into the brain after oral ingestion, OCTN1 may contribute to the alleviation of oxidative stress and promotion of neuronal differentiation via the uptake of ERGO in the brain, perhaps abating symptoms of neurological disorders. In this review, we introduce current topics on the physiological roles of OCTs with a focus on OCTN1 in neural cells and discuss its possible application to the treatment of neurological disorders.

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“…It is considered that neurodegeneration owing to oxidative stress is related to the development of various brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases (Sayre et al, 2008;Cassano et al, 2012). OCTN1 may therefore influence the development of neurodegenerative diseases via its role in transporting endogenous antioxidants.…”

mentioning

confidence: 99%

Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: Possible involvement in neuronal differentiation

Nakamichi

Taguchi

Hosotani

et al. 2012

Neurochemistry International

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Glutamatergic alterations and mitochondrial impairment in a murine model of Alzheimer disease

Cited by 86 publications

References 36 publications

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

Amyloid Beta A4 Precursor Protein-binding Family B Member 1 (FE65) Interactomics Revealed Synaptic Vesicle Glycoprotein 2A (SV2A) and Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) as New Binding Proteins in the Human Brain

Physiological Roles of Carnitine/Organic Cation Transporter OCTN1/SLC22A4 in Neural Cells

Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: Possible involvement in neuronal differentiation

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