Protein aging hypothesis of Alzheimer disease.
Alzheimer disease (AD), the most common form of aging-related neurodegenerative disorders, is associated with formation of fibrillar deposits of amyloid beta-protein (Abeta). While the direct involvement of Abeta in AD has been well documented, the relations between Abeta production, amyloid formation, and neurodegeneration remain unknown. We propose that AD is initiated by a protein aging-related structural transformation in soluble Abeta. We hypothesize that spontaneous chemical modification of aspartyl residues in Abeta to transient succinimide induces a non-native conformation in a fraction of soluble Abeta, rendering it amyloidogenic and neurotoxic. Conformationally altered Abeta is characterized by increased stability in solution and the presence of a non-native beta-turn that determines folding of Abeta in solution and the structure of Abeta subunits incorporated into amyloid fibrils. While the soluble 'non-native' Abeta is both the factor triggering the neurodegenerative cascade and the precursor of amyloid plaques, these two events result from interaction of Abeta with different sets of cellular components and need not coincide in space and time. Extensive literature data and experimental evidence are provided in support of this hypothesis.
Orpiszewski
J
J
Aprot Corporation, Carmel, Indiana 46082-3813, USA. aprot@excite.com
Schormann
N
N
Kluve-Beckerman
B
B
Liepnieks
J J
JJ
Benson
M D
MD
D000544:Alzheimer Disease / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D003500:Cyclization; D006801:Humans; D007536:Isomerism; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012995:Solubility; D013388:Succinimides / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors
D016229:Amyloid beta-Peptides; D001704:Biopolymers; D013388:Succinimides; C032620:succinimide; D001224:Aspartic Acid