title: A beta amyloidogenesis: unique, or variation on a systemic theme?
abstract: For more than a century amyloid was considered to be an interesting, unique, but inconsequential pathologic entity that rarely caused significant clinical problems. We now recognize that amyloid is not one entity. In vivo it is a uniform organization of a disease, or process, specific protein co-deposited with a set of common structural components. Amyloid has been implicated in the pathogenesis of diseases affecting millions of patients. These range from Alzheimer's disease, adult-onset diabetes, consequences of prolonged renal dialysis, to the historically recognized systemic forms associated with inflammation and plasma cell disturbances. Strong evidence is emerging that even when deposited in local organ sites significant physiologic effects may ensue. With emphasis on A beta amyloid, we review the present definition, classification, and general in vivo pathogenetic events believed to be involved in the deposition of amyloids. This encompasses the need for an adequate amyloid precursor protein pool, whether precursor proteolysis is required prior to deposition, amyloidogenic amino acid sequences, fibrillogenic nucleating particles, and an in vivo microenvironment conducive to fibrillogenesis. The latter includes several components that seem to be part of all amyloids. The role these common components may play in amyloid accumulation, why amyloids tend to be associated with basement membranes, and how one may use these findings for anti-amyloid therapeutic strategies is also examined.
authors.affiliation: Department of Pathology, Queen's University, Kingston, Ontario Canada.
authors.forename: R
authors.initials: R
authors.lastname: Kisilevsky
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000145:classification / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000502:physiology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D001485:Basement Membrane / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D010450:Endopeptidases