title: Advanced glycation end products contribute to amyloidosis in Alzheimer disease.
abstract: Alzheimer disease (AD) is characterized by deposits of an aggregated 42-amino-acid beta-amyloid peptide (beta AP) in the brain and cerebrovasculature. After a concentration-dependent lag period during in vitro incubations, soluble preparations of synthetic beta AP slowly form fibrillar aggregates that resemble natural amyloid and are measurable by sedimentation and thioflavin T-based fluorescence. Aggregation of soluble 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 advanced "glycosylation" end products (AGEs) which chemically crosslink proteins. AGE-modified beta AP-nucleation seeds further accelerated aggregation 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-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 beta-amyloid is prolonged in AD, resulting in greater accumulation of AGE modifications which in turn may act to promote accumulation of additional amyloid.
authors.affiliation: Picower Institute for Medical Research, Manhasset, NY 11030.
authors.forename: M P
authors.initials: MP
authors.lastname: Vitek
authors.forename: K
authors.initials: K
authors.lastname: Bhattacharya
authors.forename: J M
authors.initials: JM
authors.lastname: Glendening
authors.forename: E
authors.initials: E
authors.lastname: Stopa
authors.forename: H
authors.initials: H
authors.lastname: Vlassara
authors.forename: R
authors.initials: R
authors.lastname: Bucala
authors.forename: K
authors.initials: K
authors.lastname: Manogue
authors.forename: A
authors.initials: A
authors.lastname: Cerami
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000378:metabolism; D000686:Amyloidosis / Q000209:etiology* / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007700:Kinetics
chemical_list: D005947:Glucose