ADVANCED GLYCATION END-PRODUCTS CONTRIBUTE TO AMYLOIDOSIS IN ALZHEIMER-DISEASE

Alzheimer disease (AD) is characterized by deposits of an aggregated 4 2-amino-acid beta-amyloid peptide (beta AP) in the brain and cerebrova sculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic beta AP slowly form fib rillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of solu ble beta AP in these in vitro assays is enhanced by addition of small amounts of pre-aggregated beta-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 advance d ''glycosylation'' end products (AGEs) which chemically crosslink pro teins. AGE-modified beta AP-nucleation seeds further accelerated aggre gation of soluble beta AP 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-l ived proteins in vivo. In a standardized competitive ELISA, plaque fra ctions of AD brains were found to contain about 3-fold more AGE adduct s per mg of protein than preparations from healthy, age-matched contro ls. These results suggest that the in vivo half-life of beta-amyloid i s prolonged in AD, resulting in greater accumulation of AGE modificati ons which in turn may act to promote accumulation of additional amyloi d.