80 β- Amyloid sensitizes neurons to glutamate toxicity81

and also enhances glutamate release by macrophages.82 Furthermore, in neuronal culture, glutamate was shown to enhance tau gene expression83 and induce paired helical filaments similar to those found in AD.84 The hypoglutamatergic hypothesis has been extensively reviewed elsewhere (see Newcomer et al, in this issue). The ketamine model is its application. Ketamine is mainly used in the field of schizophrenia research to provoke psychotomimetic as well as cognitive effects.85-94 These studies did not all assess the same functions Inhibitors,research,lifescience,medical or use the same paradigm to assess a particular function. Despite Inhibitors,research,lifescience,medical this limitation, when these studies are summarized and the profile of ketamine SB431542 in vitro effects compared with that of AD (Figure1),60-63 the situation is the same as that for the scopolamine model: the functions affected by ketamine are affected in AD, but the reverse is not necessarily the case. Future directions The two main models proposed thus lead to some of the attentional

and memory impairment observed in AD, but do not fully reproduce Inhibitors,research,lifescience,medical the AD pattern. Two options are therefore possible. Since multiple neurotransmitter systems are affected in AD, it has been suggested95 that combination modeling through simultaneous Inhibitors,research,lifescience,medical administration of drugs that impair several neurotransmitters or different aspects of a single system could mimic the AD pattern more closely. The fewpublished studies on this strategy add mecamylamine,96 m-chlorophenylpiperazine

(mCPP),97 metergoline, or haloperidol98 to scopolamine, and report no98 or marginal96-97 cumulative effect. Although NMDA antagonists were shown to potentiate the amnesic effect of scopolamine in the rat,58 no study on this combination in humans has been published to date. Beyond the weakness of their effects, combined models are so complex that they become difficult Inhibitors,research,lifescience,medical to understand – and particularly difficult to manipulate – Cytidine deaminase in the assessment of cognitive enhancers. Another method is to take advantage of the recent advances in our understanding of AD. Currently available data support the view that neuronal and synaptic loss, rather than secondary neurotransmission disruption, is most likely responsible for cognitive changes in AD.99 They also allow attempts to integrate neurotransmitter changes into a more comprehensive theoretical framework. The cholinergic hypothesis in its current version (Figure 2) focuses on the reciprocal modulatory influences of cholinergic transmission and APP processing (reviewed in references 100 and 101). β-Amyloid (βA) is known to be neurotoxic at high (micromolar) concentrations.