Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease.
Pioneering work in the 1950s by Christian Anfinsen on the folding of ribonuclease has shown that the primary structure of a protein "encodes" all of the information necessary for a nascent polypeptide to fold into its native, physiologically active, three-dimensional conformation (for his classic review, see [Science 181 (1973) 223]). In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) appears to play a seminal role in neuronal injury and death. Recent data have suggested that the proximate effectors of neurotoxicity are oligomeric Abeta assemblies. A fundamental question, of relevance both to the development of therapeutic strategies for AD and to understanding basic laws of protein folding, is how Abeta assembly state correlates with biological activity. Evidence suggests, as argued by Anfinsen, that the formation of toxic Abeta structures is an intrinsic feature of the peptide's amino acid sequence-one requiring no post-translational modification or invocation of peptide-associated enzymatic activity.
Klein
W L
WL
Department of Neurobiology and Physiology, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University Institute for Neuroscience, Evanston, IL, USA.
Stine
W B
WB
Teplow
D B
DB
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D017510:Protein Folding; D011499:Protein Processing, Post-Translational / Q000502:physiology; D000099291:Adducins
D016229:Amyloid beta-Peptides; D002148:Calmodulin-Binding Proteins; D008715:Methionine; D009498:Neurotoxins; D010446:Peptide Fragments; C102021:ADD3 protein, human; D000099291:Adducins