FBPixel Advanced glycation end products contribute to amyloidosis in Alzheimer disease - David Perlmutter M.D.

Science

Study Title
Advanced glycation end products contribute to amyloidosis in Alzheimer disease
Publication
Proceedings of the National Academy of Sciences
Author(s)

MICHAEL P. VITEK, KESHAB BHATTACHARYA, J. MICHAEL GLENDENING, EDWARD STOPA, HELEN VLASSARA, RICHARD BUCALA, KIRK MANOGUE, AND ANTHONY CERAMI

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 invitro incubations, soluble preparations of synthetic βAP slowly form fibrilar 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-modiflied “seed” material. Over time, nonenzymatic advanced glycation also results in the gradual accumulation of a set of post translational 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 accumultion of AGE modification swhich in turn may act to promote accumulation of additional amyloid.

Date
May 1, 1994
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Alzheimer’sAdvanced Glycation End Products (AGEs)

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