Protein aging hypothesis of Alzheimer disease

Jozef Orpiszewski, Norbert Schormann, Barbara Kluve-Beckerman, Juris J. Liepnieks, Merrill D. Benson

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Abstract

Alzheimer disease (AD), the most common form of aging-related neurodegenerative disorders, is associated with formation of fibrillar deposits of amyloid β-protein (Aβ). While the direct involvement of Aβ in AD has been well documented, the relations between Aβ production, amyloid formation, and neurodegeneration remain unknown. We propose that AD is initiated by a protein aging-related structural transformation in soluble Aβ. We hypothesize that spontaneous chemical modification of aspartyl residues in Aβ to transient succinimide induces a non-native conformation in a fraction of soluble Aβ, rendering it amyloidogenic and neurotoxic. Conformationally altered Aβ is characterized by increased stability in solution and the presence of a non-native β-turn that determines folding of Aβ in solution and the structure of Aβ subunits incorporated into amyloid fibrils. While the soluble 'non-native' Aβ is both the factor triggering the neurodegenerative cascade and the precursor of amyloid plaques, these two events result from interaction of Aβ 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.

Original languageEnglish (US)
Pages (from-to)1255-1263
Number of pages9
JournalFASEB Journal
Volume14
Issue number9
StatePublished - Jun 24 2000

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Keywords

  • Amyloid β-protein
  • Amyloidosis
  • Isoaspartate
  • Succinimide

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Orpiszewski, J., Schormann, N., Kluve-Beckerman, B., Liepnieks, J. J., & Benson, M. D. (2000). Protein aging hypothesis of Alzheimer disease. FASEB Journal, 14(9), 1255-1263.