Modifications of neuronal phosphorylated τ immunoreactivity induced by NMDA toxicity

Couratier, P.; Lesort, Mathieu; Sindou, Philippe; Esclaire, Françoise; Yardin, Catherine; Hugon, Jacques

doi:10.1007/bf02815108

Cited by 52 publications

(30 citation statements)

References 56 publications

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“…Indeed, previous reports support this notion and glutamatergic transmission is severely altered by early degeneration of corticocortical connections and hippocampal projections in AD [5]. In addition, glutamatergic neurons are prone to develop neurofibrillary tangles [6] and glutamate increases the expression and phosphorylation of tau [7][8][9].…”

Section: Introductionsupporting

confidence: 51%

“…The exact role played by excitotoxicity in AD has been hotly debated. There is limited evidence that directly supports excitotoxicity in AD, but it is notable that the activation of NMDA and AMPA receptors can increase the expression of tau protein and its phosphorylation [7,8]. Given that the increase of tau protein expression and phosphorylation is one of the hallmark pathologies in AD, a signal transduction pathway which is controlled via activation of NMDA receptors may play a role in the pathogenesis of AD.…”

Section: Nmda Receptorsmentioning

confidence: 99%

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Differential Regulation of Glutamate Receptors in Alzheimer’s Disease

et al. 2002

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Selective neurodegeneration is a prominent feature in Alzheimer’s disease; however, the mechanism of neuronal death is still unclear. Nonetheless, the topographical distribution of different types of receptors is thought to contribute to the regional selective nature of neuronal degeneration. Specifically, since glutamatergic transmission is severely altered by the early degeneration of cortico-cortical connections and hippocampal projections in Alzheimer’s disease, we suspect that glutamate receptors may play a new role in the pathophysiology of disease. Here we review the salient aspects of glutamate receptor expression in Alzheimer’s disease and how their differential regulation can contribute to the selective neurodegeneration seen in the disease. Additionally, we assess the potential therapeutic value of glutamate receptors as a target for drug intervention in Alzheimer’s disease.

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Section: Introductionsupporting

confidence: 51%

Section: Nmda Receptorsmentioning

confidence: 99%

Differential Regulation of Glutamate Receptors in Alzheimer’s Disease

et al. 2002

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“…(10) Acute or chronic NMDA-induced excitotoxicity in neuronal cultures is associated with an augmented immune-labelling of phosphorylated tau proteins at serine 202 (AT8 antibody) as observed in paired helical neuro-filaments (Couratier et al, 1995;1996a). NMDA-induced cell death and elevated AT8 tau immunoreactivity is blocked significantly by NMDA receptor antagonists (Couratier et al, 1996b).…”

Section: Activation Of Nmda Receptors May Enhance Production Of Elemementioning

confidence: 99%

Neuroprotective and symptomatological action of memantine relevant for alzheimer’s disease — a unified glutamatergic hypothesis on the mechanism of action

Danysz¹,

Parsons²,

Möbius³

et al. 2000

neurotox res

224

133

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The involvement of glutamate mediated neurotoxicity in the pathogenesis of Alzheimer's disease is finding increasingly more acceptance in the scientific community. Central to this hypothesis is the assumption that in particular glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner. Such continuous mild activation leads under chronic conditions to neuronal damage. Moreover, one should consider that impairment of plasticity (learning) may result not only from neuronal damage per se but also from continuous activation of NMDA receptors. To investigate this possibility we tested whether overactivation of NMDA receptors using either non-toxic doses/concentrations of a direct NMDA agonist or through an indirect approach--decrease in magnesium concentration--produces deficits in plasticity. In fact NMDA both in vivo (passive avoidance test) and in vitro (LTP in CA1 region) impaired learning and synaptic plasticity. Under these conditions memantine which is an uncompetitive NMDA receptor antagonist with features of "improved magnesium" (voltage dependence, affinity) attenuated the deficit. The more direct proof that memantine can act as a surrogate for magnesium was obtained in LTP experiments under low magnesium conditions. In this case as well, impaired LTP was restored in the presence of therapeutically relevant concentrations of memantine (1 microM). In vivo, doses leading to similar brain/serum levels produce neuroprotection in animal models relevant for neurodegeneration in Alzheimer's disease such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. Hence, we postulate that if in Alzheimer's disease overactivation of NMDA receptors occurs indeed, memantine would be expected to improve both symptoms (cognition) and slow down disease progression because it takes over the physiological function of magnesium.

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“…A link between glutamate excitotocity and tau first was suggested by studies in cultured rat hippocampal neurons in which glutamate-induced neurodegeneration was associated with immunostaining specific for neurofibrillary tangles (90). More recently, it has been shown that acute or chronic NMDA-induced excitotoxicity in neuronal cultures augments tau production (114,136) and specifically increases tau that is phosphorylated at serine 202 (29). Since evidence suggests that neurofibrillary tangles are a critical determinant of the clinical progression of AD (12), and that augmented tau phosphorylation is prevented by NMDA receptor antagonists (30), it is conceivable that NMDA receptor-dependent effects on phosphorylated tau could promote the evolution of AD pathology.…”

Section: Nmda Receptors and Taumentioning

confidence: 99%

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

2003

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Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase in-hibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates â-amyloid (Aâ) toxicity and possibly inhibits Aâ production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists , particularly those that act by a similar channel blocking mechanism such as dis-sociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of chan-275 nel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate-an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity-while sparing synaptic responses required for normal be-havioral functioning, cognition and memory.

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Modifications of neuronal phosphorylated τ immunoreactivity induced by NMDA toxicity

Cited by 52 publications

References 56 publications

Differential Regulation of Glutamate Receptors in Alzheimer’s Disease

Differential Regulation of Glutamate Receptors in Alzheimer’s Disease

Neuroprotective and symptomatological action of memantine relevant for alzheimer’s disease — a unified glutamatergic hypothesis on the mechanism of action

The Neuropharmacological Basis for the Use of Memantine in the Treatment of Alzheimer's Disease

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