Amyloid Deposition and Influx Transporter Expression at the Blood-Brain Barrier Increase in Normal Aging

Aging is the most important single risk factor for developing Alzheimer disease. We measured amyloid-beta peptide (A beta) levels in rat cerebral cortex and hippocampus during normal aging of Brown-Norway/Fischer rats. Amyloid-beta accumulation was associated with expression of the A beta influx transporter, the receptor for advanced glycation end-products (RAGEs) at the blood-brain barrier. Rats at selected ages from 3 to 36 months were analyzed by 1) immunohistochemistry for amyloid deposition and quantitative microvessel surface area RAGE expression, 2) ELISA for cortical A beta 40 and A beta 42 concentrations, and 3) Western blotting for microvessel proteins for RAGE expression. Immunohistochemistry showed increasing accumulation of brain A beta with aging. By ELISA analysis, both A beta 40 and A beta 42 concentrations in cortical homogenates rose sharply from 9 to 12 months. The A beta 42 continued to rise up to age 30 months, whereas A beta 40 stabilized after 12 months. The expression of RAGE intially decreased between 3 and 12 months but then increased between 12 and 34 months by immunohistochemistry. On immunoblotting, RAGE decreased up to 9 months and then progressively increased up to 36 months. These data indicate an association between amyloid and microvessel RAGE during aging. An increase in capillary RAGE expression seems to play a role in the later A beta accumulation but not in the initial increase.