Alzheimer's disease (AD) like pathology following developmental lead exposure in primates and the role of aging in AD-related genes regulation in rodents and primates.

摘要

Alzheimer's disease is a progressive, irreversible neurodegenerative disease results in memory loss and dementia. The search for the etiology of sporadic AD focuses on environmental links and the role of aging. In manuscript 1, we validated our previous rodent model in primates by the following findings. (1) Developmental Pb exposure caused elevated AD-related APP, BACE1 and Sp1 mRNA expression as well as APP protein and amyloidogenic Abeta40 and Abeta42. (2) The molecular changes were accompanied by AD-like pathological changes in exposed monkey brains. (3) Pb exposure increased 8-oxo-2'-deoxyguanine in the monkey brain. (4) DNA methyltransferase activity was suppressed in exposed primates suggesting there might be altered DNA methylation profile. In manuscript 2, we compared lifetime profiles of AD-associated APP transcription, translation and procession to amyloidogenic product in non plaque-forming rodents and plaque-forming primates. We found that: (1) APP mRNA expression increase with aging in rodents, but translation to protein and procession to cleavage product thereafter were blocked. (2) APP and its cleavage product accumulated in primates despite a decreased transcription with normal aging. (3) BACE1 activity did not account for the elevated amyloidogenic Abeta in old age. This work is the first to compare lifespan changes in both non plaque-forming and plaque-forming animals.