Pharmacological models in Alzheimer's disease research

Figures & data

Figure 1. Memory dysfuction in Alzheimer's disease (AD) and after scopolamine or ketamine

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 (CAT, the acetylcholine synthesis enzyme) activity. It lowers the availability of the substrates for acetylcholine (ACh) synthesis by impairing high-affinity choline uptake and acetyl coenzyme A (acetyl CoA) production; therefore ACh release is also diminished. Choline deprivation could initiate the so-called “autocannibalism” process through which ACh neurons break down membrane phosphatidylcholine to increase choline availability. Autocannibalism could be partly responsible for neuronal loss in the basal nucleus of Meynert (BNM), medial septal nucleus (S), and nucleus of the diagonal band of Broca (DB), and for the observed decrease in muscarinic M₂ and nicotinic (N) receptor densities, which are mainly presynaptic. Muscarinic M, receptors are mainly postsynaptic and their density is not affected in Alzheimer's disease. However, they are probably dysfunctional because of receptor-G protein uncoupling, with two consequences: (i) lowered M, signal transduction favors the amyloidogenic APP processing pathway, which further aggravates uncoupling; and (ii) through loss of inhibition of mitogen-activated protein (MAP) kinase, which results in increased tau protein phosphorylation, and inhibition of phosphatase, which results in a lesser dephosporylation of tau, it favors the formation of paired helical filaments (PHF).