β-Amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus

Wu, Jin V.; Anwyl, Roger; Rowan, Michael J.

doi:10.1097/00001756-199511270-00031

Cited by 114 publications

(66 citation statements)

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“…An intrinsic age-related loss of Glu in the striatum, likely resulting in reduced Glu receptor activation and correlating with impaired cognitive performance, is consistent with literature describing cognitive impairment as a result of NMDA Glu receptor inhibition in normal healthy individuals (Krystal et al 1999;Newcomer et al 1999;Parwani et al 2005). These results do not contradict findings in other age-related diseases, such as Alzheimer's disease, where pathology may include increased Glu levels (Hoyer and Nitsch 1989;Noda et al 1999) or increased NMDA receptor sensitivity to Glu (Wu et al 1995) that may be corrected by antagonists, such as memantine. Furthermore, in contrast to the NMDA receptor channel blockers that can impair cognitive function (e.g., ketamine), memantine has faster kinetics (Rogawski et al 1991;Lipton 2005), which may explain its therapeutic benefit and tolerability.…”

Section: Discussionsupporting

confidence: 89%

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

et al. 2008

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Glutamate (Glu), the principal excitatory neurotransmitter of prefrontal cortical efferents, potentially mediates higher order cognitive processes, and its altered availability may underlie mechanisms of age-related decline in frontally based functions. Although animal studies support a role for Glu in age-related cognitive deterioration, human studies, which require magnetic resonance spectroscopy for in vivo measurement of this neurotransmitter, have been impeded because of the similarity of Glu's spectroscopic signature to those of neighboring spectral brain metabolites. Here, we used a spectroscopic protocol, optimized for Glu detection, to examine the effect of age in 3 brain regions targeted by cortical efferents-the striatum, cerebellum, and pons-and to test whether performance on frontally based cognitive tests would be predicted by regional Glu levels. Healthy elderly men and women had lower Glu in the striatum but not pons or cerebellum than young adults. In the combined age groups, levels of striatal Glu (but no other proton metabolite also measured) correlated selectively with performance on cognitive tests showing age-related decline. The selective relations between performance and striatal Glu provide initial and novel, human in vivo support for age-related modification of Glu levels as contributing to cognitive decline in normal aging.

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Section: Discussionsupporting

confidence: 89%

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

et al. 2008

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“…3d), an up-regulation of NMDA receptors is more likely. Consistent with this interpretation, acute application of recombinant A␤ has been reported to selectively up-regulate NMDA receptor-mediated, but not A MPA receptormediated, synaptic transmission in hippocampal slices (45). Conceivably, A␤-induced up-regulation of NMDA receptors Proc.…”

Section: Resultsmentioning

confidence: 73%

Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models

Hsia¹,

Masliah²,

McConlogue³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

1,049

827

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Autosomal dominant forms of familial Alzheimer's disease (FAD) are associated with increased production of the amyloid ␤ peptide, A␤42, which is derived from the amyloid protein precursor (APP). In FAD, as well as in sporadic forms of the illness, A␤ peptides accumulate abnormally in the brain in the form of amyloid plaques. Here, we show that overexpression of FAD(717 V3 F )-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques. Electrophysiological recordings from the hippocampus revealed prominent deficits in synaptic transmission, which also preceded amyloid deposition by several months. Although in young mice, functional and structural neuronal deficits were of similar magnitude, functional deficits became predominant with advancing age. Increased A␤ production in the context of decreased overall APP expression, achieved by addition of the Swedish FAD mutation to the APP transgene in a second line of mice, further increased synaptic transmission deficits in young APP mice without plaques. These results suggest a neurotoxic effect of A␤ that is independent of plaque formation.Alzheimer's disease (AD) is a progressive dementing illness in which the brain becomes littered with neuritic amyloid plaques. These plaques are associated with degenerating neuronal processes and consist primarily of fibrillar aggregates of the amyloid ␤ peptide, A␤. A␤ is derived from the amyloid protein precursor (APP), presumably via proteolytic cleavage of APP by ␤-and ␥-secretases (1). The predominant forms of A␤ are 40 (A␤40) or 42 (A␤42) amino acids in length (2). A␤42 and A␤40 appear to be generated in different intracellular compartments, and A␤42 has a greater propensity to selfaggregate into insoluble fibrils than A␤40 (3, 4). Various point mutations in three distinct genes (APP, presenilin 1, presenilin 2) have been linked to autosomal dominant forms of familial AD (FAD). Notably, all of these mutations increase the production of A␤42 (5).Although A␤ has been shown to be neurotoxic in cell culture (6-8), a causal role for A␤ in widespread neuronal degeneration in vivo remains speculative. A particularly controversial question concerns whether A␤-induced neurotoxicity requires deposition of aggregated A␤ into plaques (9-13). Transgenic mice in which full-length FAD-mutant APPs and A␤ are coexpressed at high levels develop typical neuritic amyloid plaques (14-17). However, loss of neurons so far has been identified in only one of these models (18) whereas two others showed no significant neuronal loss despite extensive cerebral A␤ deposition (19,20). No electrophysiological studies have been reported in these models.In the current study, we investigated in transgenic mice what early effects neuronal expression of full-length, FAD-mutant human APP has on the anatomy and physiology of the hippocampus, a central nervous system structure considered crucial for learning and memory. Our study demonstrates that the development ...

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“…Excessive or inappropriate activation of NMDARs can block LTP (36), and under certain circumstances A␤ can selectively enhance NMDAR-mediated currents and synaptic transmission (18,(37)(38)(39)(40), or promote increased Ca 2ϩ influx and elevate the levels of potentially toxic reactive oxygen species in an NMDARdependent manner (37,41). However, in contrast to the present findings, the inhibition of LTP by exogenous application of NMDA has been reported to be caused by Ca 2ϩ entry following activation of GluN2A-rather than GluN2B-containing NMDARs (42).…”

Section: Discussionmentioning

confidence: 99%

GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo

Klyubin

Anwyl

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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148

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β-Amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus

Cited by 114 publications

References 0 publications

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models

GluN2B subunit-containing NMDA receptor antagonists prevent Aβ-mediated synaptic plasticity disruption in vivo

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