Physiological and pathological interrelationships of amyloid beta peptide and the amyloid precursor protein.
Amyloid beta peptide (beta A4) accumulates as plaques in the brains of individuals with Alzheimer's disease and Down's syndrome, and may contribute to the cognitive decline that is a feature of these diseases. beta A4 is a normal product of cell metabolism, derived from the amyloid precursor protein (APP), but the biological functions of these molecules are not fully known. A hypothetical, descriptive model of the biological interrelationships between beta A4 and APP is presented. APPs, the soluble form of APP, which is released at the neuronal surface, and beta A4 are envisaged as physiological ligands which have reciprocal paracrine effects on neuronal growth and neurite extension. Differential expression of these factors, manifest as changes in the APPs: beta A4 ratio, may therefore have growth-promoting or growth-inhibiting effects on neurons. These effects may be mediated through separate cell-surface interactions but common intracellular effector systems, such as calcium and protein kinase C. In turn, the intracellular events may control the relative production of each ligand from APP through negative feedback loops. Disturbances of these control mechanisms may permit pathological overproduction, and hence accumulation, of beta A4. Such a model may also have therapeutic implications.
Larner
A J
AJ
University of Cambridge, Department of Anatomy, UK.
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases; D001692:Biological Transport; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D010450:Endopeptidases / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D011499:Protein Processing, Post-Translational; D012995:Solubility
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human