Alzheimer's disease: relationship between muscarinic cholinergic receptors, beta-amyloid and tau proteins.
Senile dementia is one of the most important health problems in developed countries. The main disease causing dementia is Alzheimer's disease that is characterized by the progressive deterioration of the cholinergic system, beta-amyloid production and deposition, and neurofibrillary tangle formation. Most of the reviewed data, along with data from experiments performed in our laboratory, suggest that there are no changes in the number of muscarinic receptors between Alzheimer and control brains, although the receptors expressed in Alzheimer's disease brains can be anomalous in their function. The muscarinic receptor-G-protein interaction also seems to be impaired in Alzheimer's disease compared with control brains, as well as the G-protein system, with an important decrease in the function of the Gq/11, the most important G-protein stimulating phosphoinositide hydrolysis in human brain; in addition, the second messenger system is also impaired, with a decrease in the synthesis of phosphoinositides and in the number of IP3 receptors. Muscarinic cholinergic receptors are also linked to beta-amyloid production, stimulation of the M1 subtype with agonists results in the processing of the beta-amyloid precursor protein to non-amyloidogenic products and administration of a fraction of the beta-amyloid (beta-amyloid 25-35) to rats, results in a decrease in the number of muscarinic receptors in brain. M1 agonists also decrease the phosphorylation of tau proteins, playing again a modulatory role in the pathogenesis of Alzheimer's disease. The existence of a link between beta-amyloid and tau proteins also has been reported; treatment of hippocampal neurones with beta-amyloid, or the 25-35 residue fragment, resulted in an increase in tau protein phosphorylation. The particular contribution of muscarinic receptors, beta-amyloid and tau proteins in the pathogenesis of Alzheimer's disease remains still unclear. Probably Alzheimer's disease could be due to a progressive degeneration in the relationship between the three components covered in this review.
Pavía
J
J
Department of Pharmacology, Malaga School of Medicine, Malaga University, Madrid, Spain.
de Ceballos
M L
ML
Sanchez de la Cuesta
F
F
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D011976:Receptors, Muscarinic / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D011976:Receptors, Muscarinic; D016875:tau Proteins; D019204:GTP-Binding Proteins