The pharmacology of amyloid precursor protein processing.
The possibility to understand the causes and treat the symptoms of Alzheimer's disease patients is still a great challenge. The triggering events leading to the selective neurodegeneration observed in Alzheimer's brains are not completely understood. This lack of understanding of the pathophysiological processes posses an important theoretical challenge for the rational design of pharmacological intervention. The scientific community is divided over the pathogenesis of the disease which is historically divided between 'baptists' and 'tauists'. Baptists suggest that beta-amyloid, the peptide deposited in neuritic plaques, is the cause of all damages while tauists suggest that hyperphosphorylated tau, the cytoskeletal protein that forms neurofibrillary tangles, is the culprit for the disease. This review will be focused on the pharmacological modulation of the amyloid precursor protein metabolism, with the goal of reducing the formation of beta-amyloid. Over the years such an approach has led to the identification of a complex intracellular mechanism, which may be regulated by neurotransmitters and other ligands. More recently, these efforts have contributed to the characterization of the enzymes which regulate the formation of beta-amyloid.
Racchi
Marco
M
Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy. racchi@unipv.it
Govoni
Stefano
S
D000368:Aged; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D018678:Cholinergic Agents / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D020555:GTP-Binding Protein Regulators / Q000378:metabolism; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018678:Cholinergic Agents; D004967:Estrogens; D020555:GTP-Binding Protein Regulators; D018377:Neurotransmitter Agents; D016875:tau Proteins; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human