Advanced glycation end products contribute to amyloidosis in Alzheimer disease

Michael P. Vitek, Keshab Bhattacharya, J. Michael Glendening, Edward Stopa, Helen Vlassara, Richard Bucala, Kirk Manogue, Anthony Cerami

Research output: Contribution to journalArticlepeer-review

780 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)4766-4770
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number11
DOIs
StatePublished - 24 May 1994
Externally publishedYes

Keywords

  • aggregation
  • nucleation-dependent kinetics
  • seed structure and function
  • β-amyloid peptide

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