Alzheimer Amyloid β-Peptide Inhibits the Late Phase of Long-Term Potentiation through Calcineurin-Dependent Mechanisms in the Hippocampal Dentate Gyrus

Chen, Qi-Sheng; Wei, Weizheng; Shimahara, Takeshi; Xie, Cui-Wei

doi:10.1006/nlme.2001.4034

Cited by 167 publications

(153 citation statements)

References 65 publications

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“…Consistent with our model, A␤ oligomers produced by 7PA2 cells have been previously shown to inhibit hippocampal LTP induction in vivo and in vitro and to interfere with the performance of trained rats on a memory recall task (Walsh et al, 2002Cleary et al, 2005;Klyubin et al, 2005). Furthermore, a previous study reported that FK506 prevented the ability of synthetic A␤ to inhibit LTP in hippocampus (Chen et al, 2002), suggesting that the inhibition of LTP by A␤ oligomers reflects a shift in the LTP/LTD balance rather than a direct blockade of LTP-inducing pathways.…”

Section: Mechanisms Of A␤-induced Spine Losssupporting

confidence: 88%

Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway

Shankar

Bloodgood²,

Townsend³

et al. 2007

J. Neurosci.

1,432

1,195

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Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-␤ protein (A␤) in AD, a direct link between a specific form of A␤ and synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted A␤ dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by A␤-specific antibodies or a small-molecule modulator of A␤ aggregation. Mechanistically, A␤-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDARmediated calcium influx into active spines was reduced by A␤ oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human A␤ trigger synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of A␤-induced neuronal dysfunction.

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Section: Mechanisms Of A␤-induced Spine Losssupporting

confidence: 88%

Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway

Shankar

Bloodgood²,

Townsend³

et al. 2007

J. Neurosci.

1,432

1,195

View full text Add to dashboard Cite

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“…Similarly, the enrichment of metabolic pathways, organismal systems including nervous and immune system pathways, and common signaling pathways of the environmental information processing category is also expected and well-supported in the literature [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Interestingly, several genetic information processing pathways, including cell cycle regulation and DNA replication and repair, were found to be enriched.…”

Section: Snp-enriched Pathways and Associated Crosstalkssupporting

confidence: 56%

Characterizing Gene and Protein Crosstalks in Subjects at Risk of Developing Alzheimer’s Disease: A New Computational Approach

et al. 2017

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Alzheimer's disease (AD) is a major public health threat; however, despite decades of research, the disease mechanisms are not completely understood, and there is a significant dearth of predictive biomarkers. The availability of systems biology approaches has opened new avenues for understanding disease mechanisms at a pathway level. However, to the best of our knowledge, no prior study has characterized the nature of pathway crosstalks in AD, or examined their utility as biomarkers for diagnosis or prognosis. In this paper, we build the first computational crosstalk model of AD incorporating genetics, antecedent knowledge, and biomarkers from a national study to create a generic pathway crosstalk reference map and to characterize the nature of genetic and protein pathway crosstalks in mild cognitive impairment (MCI) subjects. We perform initial studies of the utility of incorporating these crosstalks as biomarkers for assessing the risk of MCI progression to AD dementia. Our analysis identified Single Nucleotide Polymorphism-enriched pathways representing six of the seven Kyoto Encyclopedia of Genes and Genomes pathway categories. Integrating pathway crosstalks as a predictor improved the accuracy by 11.7% compared to standard clinical parameters and apolipoprotein E ε4 status alone. Our findings highlight the importance of moving beyond discrete biomarkers to studying interactions among complex biological pathways.

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“…We hypothesize that calcineurin could become activated following TNF-α application by a rise in Ca 2+ from intracellular calcium stores and negatively affect the induction of LTP. Interestingly inhibition of calcineurin has been found to attenuate amyloid-beta-mediated inhibition of late-LTP in the dentate gyrus (Chen et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…This paper presents the first evidence that ryanodine, an inhibitor of ryanodine receptor Ca 2+ -release channels significantly reversed the inhibition of LTP by TNF-α, while having no effect on the induction of LTP at the same concentration. Amyloid-β, which has recently being proposed to inhibit LTP through the activation of the TNF-R1 (p55) receptor (Wang et al, 2005), has previously been shown to reduce NMDA EPSCs (Chen et al, 2002;Snyder et al, 2005) and lead to transient intracellular Ca 2+ rises in cultured hippocampal neurons (Smith et al, 2001). It would be intriguing to speculate if amyloid-β mediated inhibition of LTP could be similarly blocked with ryanodine.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

Cumiskey¹,

Butler²,

Moynagh³

et al. 2007

Brain Research

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Pro-inflammatory cytokines are known to be elevated in several neuropathological states that are associated with learning and memory. We have previously demonstrated in our laboratory that the inhibition of long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus, by tumor necrosis factor (TNF)-α, represents a biphasic response, an early phase dependent on p38 mitogen activated protein kinase (MAPK) activation and a later phase, possible dependent on protein synthesis. Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated. This study investigated if metabotropic glutamate receptors (mGluRs) are functionally linked to the inhibitory effect of TNF-α on LTP in the rat dentate gyrus in vitro. We report that the impairment of early-LTP by TNF-α is significantly attenuated by prior application of the group I/II mGluR antagonist MCPG and more specifically the mGluR5 antagonist MPEP. Since TNF-α is now known to cause transient increases in intracellular Ca 2+ levels from ryanodine-sensitive stores, we explored the possibility that disruption of intracellular Ca 2+ homeostasis could be involved.Ryanodine was found to significantly reverse the inhibition of LTP by TNF-α. From these studies we propose that the TNF-α inhibition of LTP is dependent upon the activation of TNFR1 and mGlu5-receptors. Importantly this study provides the first proof of the involvement of ryanodine-sensitive intracellular Ca 2+ stores in TNF-α mediated inhibition of LTP. IntroductionThe pro-inflammatory cytokine tumor-necrosis factor (TNF)-α is elevated in the brain in a number of neuropathological states including trauma, ischemia, Parkinson's disease, multiple sclerosis and HIV-associated dementia (Iida et al., 2000;Kassiotis and Kollias, 2001;Sriram et al., 2002). The signaling mechanism underlying the ability of TNF-α to cause the cognitive dysfunction associated with many of these conditions has been probed, but to date no clear mechanistic understanding has been reached. TNF-α and IL-1β at pathophysiological levels have been shown by many authors to inhibit long-term potentiation (LTP) in the CA1 and the dentate gyrus regions of the rat hippocampus (Cunningham et al., 1996;Murray and Lynch, 1998;Tancredi et al., 1992) but not by others (Stellwagen and Malenka, 2006). IL-1β has been shown to depress NMDAreceptor mediated field potentials in the dentate gyrus (Coogan B R A I N R E S E A R C H 1 1 3 6 ( 2 0 0 7 ) 1 3 -1 9 ⁎ Corresponding author.

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Alzheimer Amyloid β-Peptide Inhibits the Late Phase of Long-Term Potentiation through Calcineurin-Dependent Mechanisms in the Hippocampal Dentate Gyrus

Cited by 167 publications

References 65 publications

Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway

Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway

Characterizing Gene and Protein Crosstalks in Subjects at Risk of Developing Alzheimer’s Disease: A New Computational Approach

Evidence for a role for the group I metabotropic glutamate receptor in the inhibitory effect of tumor necrosis factor-α on long-term potentiation

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