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b-amyloid (Ab) is widely accepted to be one of the major pathomechanisms underlying Alzheimer's disease (AD), although there is presently lively debate regarding the relative roles of particular species/forms of this peptide. Most recent evidence indicates that soluble oligomers rather than plaques are the major cause of synaptic dysfunction and ultimately neurodegeneration. Soluble oligomeric Ab has been shown to interact with several proteins, for example glutamatergic receptors of the NMDA type and proteins responsible for maintaining glutamate homeostasis such as uptake and release. As NMDA receptors are critically involved in neuronal plasticity including learning and memory, we felt that it would be valuable to provide an up to date review of the evidence connecting Ab to these receptors and related neuronal plasticity. Strong support for the clinical relevance of such interactions is provided by the NMDA receptor antagonist memantine. This substance is the only NMDA receptor antagonist used clinically in the treatment of AD and therefore offers an excellent tool to facilitate translational extrapolations from in vitro studies through in vivo animal experiments to its ultimate clinical utility. AbbreviationsAA, arachidonic acid; Ab, b-amyloid; AChEI, AChEI inhibitor; AD, Alzheimer's disease; ADDLs, Ab-derived diffusible ligands; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; CA1, Cornu ammonis area 1; CamKII, Ca 2+ /calmodulin-dependent protein kinases II; CaMKK b, calmodulin-dependent protein kinase-b; CDK5, cell division protein kinase 5; CPP, 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid; CREB, cAMP response element-binding; D-APV, D-AP5, D-amino-phospovaleric acid; DG, dentate gyrus; EAAT2, excitatory amino acid transporter 2; FB, Ab; fibril; GFAP, glial fibrillary acidic protein; GLAST, glial glutamate transporter; GLT-1, glutamate transporter 1; GSK-3b, glycogen synthase kinase 3b; HNE, 4-hydroxy-2-nonenal; iNOS, inducible NOS; IR, insulin receptor; KPI, Kunitz protease inhibitory domain; KPI-APPs, KPI containing APPs; LTD, long-term depression; LTP, long-term potentiation; mGluR5, metabotropic glutamate receptor 5; MoA, mechanism of action; MWM, Morris water maze; NBM, nucleus basalis of Meynert; NFTs, neurofibrillary tangles; NR2B, NMDA receptor subunit; p-, phosphorylated; PF, protofibril; PFC, prefrontal cortex; PLA, phospholipase A; PMA, phorbol myristate acetate; PP2B, protein phosphatase 2B; PS, population spike; PS1, presenilin 1; PSD-95, post-synaptic anchoring protein 95; PTP, post-tetanic potentiation; ROS, reactive oxygen species; sAPP, soluble amyloid precursor protein; ATPase Na Pathophysiology of Alzheimer's diseaseThe pathophysiology of Alzheimer's disease (AD) is characterized by chronic, progressive neurodegeneration. The precise aetiology of AD is still not fully clarified but is known to be complex and multifactorial, with a notable overlap between familial and non-familial forms but also with different forms of dementia such as vascular demen...

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There is increasing evidence for the involvement of glutamate-mediated neurotoxicity in the pathogenesis of Alzheimer's disease (AD). We suggest that glutamate receptors of the N-methyl-D-aspartate (NMDA) type are overactivated in a tonic rather than a phasic manner in this disorder. This continuous mild activation may lead to neuronal damage and impairment of synaptic plasticity (learning). It is likely that under such conditions Mg(2+) ions, which block NMDA receptors under normal resting conditions, can no longer do so. We found that overactivation of NMDA receptors using a direct agonist or a decrease in Mg(2+) concentration produced deficits in synaptic plasticity (in vivo: passive avoidance test and/or in vitro: LTP in the CA1 region). In both cases, memantine-an uncompetitive NMDA receptor antagonists with features of an 'improved' Mg(2+) (voltage-dependency, kinetics, affinity)-attenuated this deficit. Synaptic plasticity was restored by therapeutically-relevant concentrations of memantine (1 microM). Moreover, doses leading to similar brain/serum levels provided neuroprotection in animal models relevant for neurodegeneration in AD such as neurotoxicity produced by inflammation in the NBM or beta-amyloid injection to the hippocampus. As such, if overactivation of NMDA receptors is present in AD, memantine would be expected to improve both symptoms (cognition) and to slow down disease progression because it takes over the physiological function of magnesium.