Cytotoxic Intermediates in the Fibrillation Pathway: Aβ Oligomers in Alzheimer’s Disease as a Case Study

Research output: Chapter in Book/Report/Conference proceedingChapter


Multiple diseases, as diverse as diabetes and mad cow disease, exhibit accumulations of abnormal protein fibrils. Generically referred to as “amyloid,” these self-assembling fibrils typically have been considered the pathogenic molecules that cause cellular degeneration (toxins, not just tombstones). A prominent example is the “amyloid cascade hypothesis” proposed for Alzheimer’s disease (Hardy and Higgins, 1992). Fibrils, however, are not the only toxins generated by protein self-association, probably in some cases not even the most relevant ones. We now know of toxic subfibrillar species—soluble oligomers and protofibrils. The emerging hypothesis considered here is that these novel subfibrillar assemblies, the hidden toxins, constitute significant pathogenic molecules in diseases of fibrillogenic proteins.
Clues leading to this hypothesis have come in many instances from studies of Aβ (Klein et al., 2001), the fibrillogenic peptide responsible for amyloid plaques in Alzheimer’s disease (AD). Alzheimer’s disease is the most common form of dementia in the elderly, affecting 10% of individuals older than 65 (Hebert et al., 2003) and more than 25 million individuals world-wide. This chapter examines the investigation of Aβ’s role in AD essentially as a case study. Its objectives are to (1) review the link between Alzheimer’s dementia and fibrillogenic proteins and show that pathogenesis truly involves Aβ; (2) show how key problems in the amyloid cascade hypothesis disappear with the discovery of subfibrillar Aβ assemblies; (3) discuss cellular mechanisms of the new toxins that explain why AD is a disease of memory loss; (4) consider data that clinically substantiate a new, oligomerinitiated amyloid cascade hypothesis; (5) assess whether the impact of subfibrillar toxins can provide a broad mechanism applicable to multiple fibrillogenic proteins; (6) evaluate emerging implications for therapeutics and diagnostics.
At present, no cause for AD has been established; there are no effective therapeutics, and no clinical diagnostics exist. This situation, however, is rapidly changing. New insights into disease mechanisms and remarkable new therapeutic antibody strategies give us cause for optimism.
Original languageEnglish (US)
Title of host publicationProtein Misfolding, Aggregation, and Conformational Diseases
EditorsVladimir N Uversky, Anthony L Fink
Number of pages22
ISBN (Electronic)978-0-387-25919-2
ISBN (Print)978-0-387-25918-5
StatePublished - 2006

Publication series

NameProtein Reviews


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