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The cognitive and related symptoms of Alzheimer's disease are mainly attributable to synaptic failure. Here we review recent research on how the Alzheimer's disease amyloid ß-protein (Aß) affects glutamate receptors and fast excitatory synaptic transmission and plasticity of that transmission. l-glutamate, the main excitatory neurotransmitter in the brain, has long been implicated in causing NMDA receptor-mediated excitotoxicity leading to neurodegeneration in the late stages of the disease. However there is now extensive evidence that soluble Aß oligomers disrupt synaptic transmission and especially synaptic plasticity via non-excitotoxic glutamatergic mechanisms. New data highlight the relatively selective involvement of certain glutamate receptor subtypes including GluN2B (NR2B) subunit-containing NMDA receptors and mGlu5 receptors. Aß exerts direct and indirect effects on synaptic plasticity-related glutamate receptor signaling and trafficking between different neuronal compartments. For example, Aß-induced ectopic NMDA and mGlu receptor-mediated signaling coupled with caspase-3 activation may cause inhibition of long-term potentiation and facilitation of long-term depression. Intriguingly, some of the disruptive synaptic actions of Aß have been found to be dependent on endogenous tau located in dendrites or spines. Given the role of glutamatergic transmission in regulating Aß production and release, future therapies targeting glutamate offer the opportunity to remedy both mis-processing of Aß and cellular mechanisms of synaptic failure in early AD., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Soluble amyloid-β protein (Aβ) may cause cognitive impairment in Alzheimer's disease in the absence of significant neurodegeneration. Here, the ability of the NMDA receptor (NMDAR) antagonist memantine to prevent synthetic Aβ-mediated rapid functional deficits in learned behavior and synaptic plasticity was assessed in the rat. In vitro, pretreatment with a clinically relevant, NMDAR blocking concentration of memantine partially inhibited the induction of long-term potentiation (LTP) in the dentate gyrus and prevented further inhibition caused by exposure to Aβ(1-42). Whereas systemic injection with memantine alone inhibited LTP in the CA1 area in vivo, a subthreshold dose partially abrogated the inhibition of LTP by intracerebroventricular soluble Aβ(1-42). Similarly, systemic treatment with memantine alone impaired performance of an operant learning task and a subthreshold dose prevented the Aβ(1-42)-mediated increase in perseveration errors. The acute protection afforded by memantine, albeit in a narrow dose range, against the rapid disruptive effects of soluble Aβ(1-42) on synaptic plasticity and learned behavior strongly implicate NMDAR-dependent reversible dysfunction of synaptic mechanisms in Aβ-mediated cognitive impairment., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Beta-amyloid (Abeta) is the main component of the extracellular plaques present in patients with Alzheimer's disease (AD) and studies have shown that exogenous application of Abeta results in neurodegeneration. As a model of the neurodegenerative action of Abeta, we have previously shown that acutely applied Abeta inhibits the induction of LTP in the hippocampus in vitro. In the present studies, we have studied the effect of beta-adrenoceptor activation on the Abeta inhibition of LTP. Pharmacological activation of beta2 adrenoceptors, but not of beta1 adrenoceptors, was found to prevent the Abeta evoked inhibition of LTP in the dentate gyrus of adult animals. The prevention of the effect of Abeta was shown to occur via the cAMP/PKA signaling pathway as the adenylate cyclase-stimulating agent forskolin prevented the Abeta inhibition of LTP, an action prevented by the PKA inhibitor, Rp-8-Br-cAMPs. We suggest microglia as a likely site of action of the neuroprotective effect of beta2 adrenoceptor activation. Therapeutic treatment for AD may include agents that activate beta2 receptors and elevate cAMP.

Beta-amyloid (Abeta) is the principal component of the extracellular plaques present in patients with Alzheimer's disease. Several studies have recently shown that acutely applied Abeta inhibits the induction of LTP in the hippocampus. In the present studies, we have investigated the role of integrins in such Abeta-mediated block of LTP in the dentate gyrus in vitro and in the CA1 in vivo. Selective antibodies to the alpha v integrin subunit were found to prevent the Abeta inhibition of LTP, both in the dentate gyrus in vitro and in the CA1 in vivo. In contrast, two control antibodies did not prevent such action of Abeta. In addition, a small molecule nonpeptide antagonist of alpha v-containing integrins and two other antagonistic ligands of integrins, superfibronectin and the disintegrin echistatin, also prevented the Abeta inhibition of LTP. These studies indicate that alpha v integrins may be important mediators of synaptic dysfunction prior to neurodegeneration in Alzheimer's disease.

2,5-Hexanedione (2,5-HD), the major common neurotoxic metabolite of n-hexane and methyl n-butyl ketone, causes a delayed neuropathy with associated sensorimotor impairments. The question arises as to whether specific cognitive deficits occur even prior to changes in sensorimotor ability. The present experiments examined the effects of 2,5-HD on spatial navigation of rats in a water maze at levels/times that did not affect spontaneous exploratory motor activity in an open field holeboard apparatus. Exposure to 1% 2,5-HD in the drinking water for 2 weeks did not significantly affect escape learning, as measured by latency to find a hidden platform. However, 2,5-HD treated animals were impaired in the use of a spatial strategy during a recall test. A similar impairment in spatial memory was observed after i.p. injection of 500 mg/kg/day 2,5-HD for 4 days, in the absence of significant changes in sensorimotor ability or weight loss. Thus 2,5-HD may mediate some of the cognitive effects of hexacarbons and these changes can occur prior to the development of motor symptoms.

The authors assessed the usefulness of event-related potentials (ERP) and flash visual evoked potentials (FVEP) as prognostic markers in a sample of 25 subjects with probable Alzheimer's disease (AD). ERP and FVEP recordings were obtained from 21 and 23 subjects, respectively. Ranking of the annual rate of change in cognitive scales vs. baseline ERP/FVEP latencies was compared, and those with longer FVEP N(2) component latencies showed slower subsequent rates of decline (tau=0.32; z=2.16; P=0.015), suggesting that further study of FVEP responses as prognostic markers in AD is warranted.

Ultrasonic (22 kHz) vocalisation in response to a mildly aversive foot shock was measured in the dark compartment of a light-dark box both immediately and 24 h after the shock. Gepirone (1 and 5 mg/kg, IP) produced a reduction in the duration of vocalisation at both times. Although a metabolic inhibitor, proadifen (40 mg/kg) did not reduce this effect of gepirone, the gepirone hepatic metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP, 1 mg/kg), was also active in the test. Performance of a 24 h step-through passive avoidance task was impaired by gepirone only at a dose, 5 mg/kg, which also reduced spontaneous locomotor and rearing activity in the apparatus. It would appear that mild foot shock-evoked ultrasonic vocalisation may provide a more sensitive indicator of the effect of gepirone and related drugs on the affective response of rats to aversive stimulation.