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-β peptide (Aβ) levels in rat cerebral cortex and hippocampus during normal aging of Brown-Norway/Fischer rats. Amyloid-β accumulation was associated with expression of the Aβ 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) immunohis-tochemistry for amyloid deposition and quantitative microvessel surface area RAGE expression, 2) ELISA for cortical Aβ40 and Aβ42 concentrations, and 3) Western blotting of microvessel proteins for RAGE expression. Immunohistochemistry showed increasing accumulation of brain Aβ with aging. By ELISA analysis, both Aβ40 and Aβ42 concentrations in cortical homogenates rose sharply from 9 to 12 months. The Aβ42 continued to rise up to age 30 months, whereas Aβ40 stabilized after 12 months. The expression of RAGE initially 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 Aβ accumulation but not in the initial increase.