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Protein aging hypothesis of Alzheimer disease

JOZEF ORPISZEWSKI^*1, NORBERT SCHORMANN, BARBARA KLUVE-BECKERMAN, JURIS J. LIEPNIEKS and MERRILL D. BENSON^,

^* Aprot Corporation, Carmel, Indiana 46082-3813, USA;
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; and
Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana 46202, USA

¹Correspondence: Aprot Corporation, P.O. Box 3813, Carmel, IN 46082-3813, USA. E-mail: aprot{at}excite.com

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

Key Words: amyloid ß-protein • succinimide • isoaspartate • amyloidosis

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