Advanced glycation end products contribute to amyloidosis in Alzheimer disease.
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.
Vitek
M P
MP
Picower Institute for Medical Research, Manhasset, NY 11030.
Bhattacharya
K
K
Glendening
J M
JM
Stopa
E
E
Vlassara
H
H
Bucala
R
R
Manogue
K
K
Cerami
A
A
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
D005947:Glucose