103-105 Studies on the possible inhibitory effect of βA on CAT activity104-106 gave divergent results. βA appears to exert its effect on ACh synthesis and release through depletion of ACh precursors. It has been shown to disrupt the activity of pyruvate dehydrogenase,106 which generates acetyl coenzyme A (CoA) from pyruvate and was found to be decreased in the cortex of AD patients,107 and to inhibit highaffinity choline uptake.104 This could have an indirect neurotoxic effect, since Inhibitors,research,lifescience,medical cholinergic neurons deprived of choline have been shown to break down phosphatidylcholine from intracellular organelle membranes

to provide additional choline.108 Figure 2. Amyloid precursor protein (APP) is processed either by β-secretase into a nonamyloidogenic pathway or by β- and γ-secretases to produce β-amyloid peptide (βA). βA could decrease choline acetyltransferase … Although there is no general consensus (see reference 109 for review), it is thought that postsynaptic muscarinic Inhibitors,research,lifescience,medical Mi acetylcholine receptor (AChR) density is unchanged in AD, while those of presynaptic M2 and nicotinic AChRs are reduced.110,111 It has been Inhibitors,research,lifescience,medical shown that activation of protein kinase C through Mj (and M3) AChRs lowers βA production by favoring the nonamyloidogenic processing of APP112,113

Despite their unchanged density, M1 receptors could be dysfunctional114,115 because of defective coupling to Gq/11 proteins.116 This could lead to increased βA production, which would further impair

M1 AChR signal transduction.117 M1 AchR-G protein uncoupling could also favor protein tau phosphorylation and thus paired helical Temsirolimus filament formation through disinhibition Inhibitors,research,lifescience,medical of mitogen-activated protein (MAP) kinases118 and decreased efficiency of taudephosphorylation.119 Despite the uncertainties that remain, it is clear that the cholinergic deficiency can no longer be seen as a late consequence of neuropathological Inhibitors,research,lifescience,medical changes, but at least as a contributor to the cascade of events leading to fullblown dementia. The glutamatergic hypothesis has also been revisited. Its current version (see Newcomer et al, in this issue) reconciles the former hyper- and hypoglutamatergic hypotheses by proposing a two-stage process. SB-3CT In the first stage, βA increases the sensitivity of NMDA receptors to normal concentrations of glutamate, leading to destruction of NMDA-bearing GABAergic (GABA: gamma-aminobutyric acid), noradrenergic (NE), and serotonergic (5-HT) neurons, which have an inhibitory action on basal forebrain cholinergic, anterior thalamic glutamatergic, and cortical neuropeptide Y (NPY) neurons either directly (GABA, NE) or through activation of GABA neurons (5-HT). This loss of inhibition leads to hyperstimulation of cortical and corticolimbic neurons, which then degenerate, as do the hyperactive cholinergic, glutamatergic, and NPY neurons.