The Role of Advanced Glycation End Products in Brain Aging

Date

2007-10-01

Authors

Thangthaeng, Nopporn

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Abstract

Thangthaeng, Nopporn, The Role of Advanced Glycation End Products in Brain Aging. Doctor of Philosophy (Biomedical Sciences), October, 2007, 178 pp., 9 tables, 6 figures, bibliography, 213 titles. Glycoxidation is a process of post-translational modification of proteins, involving both glycation and oxidation that ultimately generated advanced glycation end products (AGEs). Glycoxidation, which pay promote oxidative stress and disrupt protein structure and function, is hypothesized to be responsible for pathological conditions related to aging, diabetes, neurodegenerative diseases, and degenerative ophthalmic diseases. Previous studies have demonstrated that AGEs accumulate in the brains of aged animals and humans, yet few studies have directly addressed the possibility that AGEs are a cause of age-related brain dysfunction. Therefore, the overall purpose of the present studies was to examine the role AGEs in normal brain again and the associated decline in cognitive and psychomotor function. In order to achieve the goals, two different approaches were taken. The first approach involved (i) determining whether or not AGEs accumulated in different regions of the brain as a function of age and (ii) determining whether these changes were correlated with individual differences in the ability of old mice to perform in tests of cognitive and psychomotor function. Age-associated accumulation of CML, a predominant form of AGEs in vivo, and expression of receptor for AGEs (RAGE) protein, inferred from densitometry quantification of immunoblots in different regions of the brain, were assessed by comparing groups of 8-or 25-month old mice. The 25-month-old mice were administered a series of behavioral tests to assess cognitive and psychomotor function prior to assessment of glycation status. In the second approach, groups of mature (6 mos) and older mice (18 mos) were fed with a control diet or a diet enriched with galactose (49% of caloric content), an intervention that was expected to promote formation of AGEs. The mice were subsequently tested for impairment of their cognitive and psychomotor functions after 8 weeks on the assigned diet. Upon completion of the behavioral tests (after 14 weeks on diet), amounts of CML and RAGE protein were assessed through densitometric analyses of the immunoblots. The main findings from the first approach were that (i) there was a robust increase in CML content and expression of RAGE protein in the aged mouse brain that occurred in a region-specific manner; (ii) the relative amounts of CML and RAGE were not closely associated with the degree of age-related impairment of mice tested for brain function. The main findings from the second approach were that high dietary galactose: (i) failed to induce aged-like behavioral impairments in young/mature mice; (ii) exacerbated age-related impairment of some psychomotor functions and (iii) had no significant effects on glycation status or oxidative damage. Comparison of the experimental outcomes from the first and second approaches was complicated by a difference in the fat content of the diets fed to the mice in the two studies, which had an apparent effect on the amounts of AGEs and protein oxidation present in young mice. However, considering the results of the two studies independently warrants the following conclusions: (i) Amounts of AGEs do not predict individualized brain aging as assessed by neurobehavioral impairment and may instead by largely reflective of chronological age. (ii) Diets enriched with galactose may produce deleterious effects in older mice that do not involve a change in oxidative damage or glycation status. Overall, these studies provide little support for a specific role of glycoxidation in normal brain aging. It is impossible that the extent of accrual of AGEs in the normally aging brain is insufficient to affect cellular function, whereas larger accumulations of AGEs may be associated with various pathological conditions discussed in the literature.

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