Synaptic Autoregulation by Metalloproteases and γ-Secretase

Restituito, Sophie; Khatri, Latika; Mathews, Paul M.; Liu, Xin; Weinberg, Richard J.; Ziff, Edward B.

doi:10.1523/jneurosci.2513-11.2011

Cited by 63 publications

(73 citation statements)

References 52 publications

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“…6A). These findings are especially interesting in light of recent findings that there is synaptic autoregulation by NMDA-induced metalloprotease-and ␥-secretasedependent proteolysis (32). ␥-Secretase-dependent release of the LRP1-ICD is increased by NMDA (Fig.…”

Section: Nmda-dependent Degradation Of Psd-95 Is Delayed and Reduced mentioning

confidence: 69%

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Modulates N-Methyl-d-aspartate (NMDA) Receptor-dependent Intracellular Signaling and NMDA-induced Regulation of Postsynaptic Protein Complexes

Nakajima

Kulik

Frotscher

et al. 2013

Journal of Biological Chemistry

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Background: Neuronally LRP1-deficient mice show severe neurological signs and symptoms. Results: Neuronal LRP1 is cleaved by ␥-secretase and regulates NMDA-dependent signaling and protein turnover. Conclusion: LRP1 modulates postsynaptic protein complexes and thus has the potential to influence synaptic transmission. Significance: This might explain why neuronal LRP1 is essential in vivo and shed light on its genetic association with neurodegenerative disease (i.e. Alzheimer disease).

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Section: Nmda-dependent Degradation Of Psd-95 Is Delayed and Reduced mentioning

confidence: 69%

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Modulates N-Methyl-d-aspartate (NMDA) Receptor-dependent Intracellular Signaling and NMDA-induced Regulation of Postsynaptic Protein Complexes

Nakajima

Kulik

Frotscher

et al. 2013

Journal of Biological Chemistry

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“…To confirm that the increase in MMPs mediated the A␤-induced disruptions in TJs, we cotreated bEnd.3 cells with A␤ 1-42 and the inhibitor GM6001, which prevents the conversion of pro-MMPs to active forms of matrix-degrading MMPs (Restituito et al, 2011). In the presence of GM6001, A␤ 1-42 -induced dysregulation of ZO-1 distribution was attenuated in a dosedependent manner (Fig.…”

Section: A␤ 1-42 -Induced Tj Alterations Are Attenuated By Gm6001 Andmentioning

confidence: 86%

A 1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling

Kook

Hong

Moon

et al. 2012

Journal of Neuroscience

226

173

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The blood-brain barrier (BBB), which is formed by adherens and tight junctions (TJs) of endothelial cells, maintains homeostasis of the brain. Disrupted intracellular Ca 2ϩ homeostasis and breakdown of the BBB have been implicated in the pathogenesis of Alzheimer's disease (AD). The receptor for advanced glycation end products (RAGE) is known to interact with amyloid ␤-peptide (A␤) and mediate A␤ transport across the BBB, contributing to the deposition of A␤ in the brain. However, molecular mechanisms underlying A␤-RAGE interaction-induced alterations in the BBB have not been identified. We found that A␤ 1-42 induces enhanced permeability, disruption of zonula occludin-1 (ZO-1) expression in the plasma membrane, and increased intracellular calcium and matrix metalloproteinase (MMP) secretion in cultured endothelial cells. Neutralizing antibodies against RAGE and inhibitors of calcineurin and MMPs prevented A␤ 1-42 -induced changes in ZO-1, suggesting that A␤-RAGE interactions alter TJ proteins through the Ca 2ϩ -calcineurin pathway. Consistent with these in vitro findings, we found disrupted microvessels near A␤ plaque-deposited areas, elevated RAGE expression, and enhanced MMP secretion in microvessels of the brains of 5XFAD mice, an animal model for AD. We have identified a potential molecular pathway underlying A␤-RAGE interaction-induced breakage of BBB integrity. This pathway might play an important role in the pathogenesis of AD.

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“…Hippocampal primary neurons were carried out by the previously described method (Restituito et al 2011). Neurons were isolated from embryonic day 19 Sprague Dawley (Charles River).…”

Section: Rat Hippocampal Neuron Cultures and Drug Treatmentmentioning

confidence: 99%

“…Neurons were isolated from embryonic day 19 Sprague Dawley (Charles River). To inhibit calcineurin or PP1 activity, 5 mM FK506 (Tocris Biosciences) or 500 nM okadaic acid (Tocris Biosciences) was treated to DIV14 neurons for 12 h. After treatment, whole-cell lysates were collected from cultured hippocampal neurons as shown previously (Restituito et al 2011) and applied to immunoblots.…”

Section: Rat Hippocampal Neuron Cultures and Drug Treatmentmentioning

confidence: 99%

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Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

et al. 2016

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Phosphorylation of GluA1, a subunit of AMPA receptors (AMPARs), is critical for AMPAR synaptic trafficking and control of synaptic transmission. cGMP-dependent protein kinase II (cGKII) mediates this phosphorylation, and cGKII knockout (KO) affects GluA1 phosphorylation and alters animal behavior. Notably, GluA1 phosphorylation in the KO hippocampus is increased as a functional compensation for gene deletion, while such compensation is absent in the prefrontal cortex. Thus, there are brain region-specific effects of cGKII KO on AMPAR trafficking, which could affect animal behavior. Here, we show that GluA1 phosphorylation levels differ in various brain regions, and specific behaviors are altered according to region-specific changes in GluA1 phosphorylation. Moreover, we identified distinct regulations of phosphatases in different brain regions, leading to regional heterogeneity of GluA1 phosphorylation in the KO brain. Our work demonstrates region-specific changes in GluA1 phosphorylation in cGKII KO mice and corresponding effects on cognitive performance. We also reveal distinct regulation of phosphatases in different brain region in which region-specific effects of kinase gene KO arise and can selectively alter animal behavior.

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Synaptic Autoregulation by Metalloproteases and γ-Secretase

Cited by 63 publications

References 52 publications

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Modulates N-Methyl-d-aspartate (NMDA) Receptor-dependent Intracellular Signaling and NMDA-induced Regulation of Postsynaptic Protein Complexes

Low Density Lipoprotein Receptor-related Protein 1 (LRP1) Modulates N-Methyl-d-aspartate (NMDA) Receptor-dependent Intracellular Signaling and NMDA-induced Regulation of Postsynaptic Protein Complexes

A 1-42-RAGE Interaction Disrupts Tight Junctions of the Blood-Brain Barrier Via Ca2+-Calcineurin Signaling

Brain region-specific effects of cGMP-dependent kinase II knockout on AMPA receptor trafficking and animal behavior

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