Advanced Glycation End Products Contribute to Amyloidosis in Alzheimer Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 11; pp. 4766 - 4770
• Main Authors: Vitek, Michael P., Bhattacharya, Keshab, Glendening, J. Michael, Stopa, Edward, Vlassara, Helen, Bucala, Richard, Manogue, Kirk, Cerami, Anthony
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 24.05.1994; National Acad Sciences; National Academy of Sciences
• Subjects: Acetates; Adducts; Aggregation; Alzheimer Disease - complications; Alzheimer Disease - metabolism; Alzheimer's disease; Alzheimers disease; Amino acids; Amyloidosis - etiology; Amyloidosis - metabolism; Amyloids; Biochemistry; Brain - metabolism; Enzyme-Linked Immunosorbent Assay; Glucose - metabolism; Glycosylation; Half lives; Humans; Kinetics; Monomers; Seeding; Sodium
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.11.4766

Alzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid β-amyloid peptide (βAP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic βAP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble βAP in these in vitro assays is enhanced by addition of small amounts of pre-aggregated β-amyloid "seed" material. We also have prepared these seeds by using a naturally occurring reaction between glucose and protein amino groups resulting in the formation of advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified βAP-nucleation seeds further accelerated aggregation of soluble βAP compared to non-modified "seed" material. Over time, nonenzymatic advanced glycation also results in the gradual accumulation of a set of posttranslational covalent adducts on long-lived proteins in vivo. In a standardized competitive ELISA, plaque fractions of AD brains were found to contain about 3-fold more AGE adducts per mg of protein than preparations from healthy, age-matched controls. These results suggest that the in vivo half-life of β-amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid.