Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD.
The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic beta-amyloid (Abeta) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (beta-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.
Wu
Jinfang
J
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Basha
Md Riyaz
MR
Brock
Brian
B
Cox
David P
DP
Cardozo-Pelaez
Fernando
F
McPherson
Christopher A
CA
Harry
Jean
J
Rice
Deborah C
DC
Maloney
Bryan
B
Chen
Demao
D
Lahiri
Debomoy K
DK
Zawia
Nasser H
NH
D000367:Age Factors; D000375:Aging; D000544:Alzheimer Disease / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007136:Immunoglobulins / Q000378:metabolism; D007854:Lead / Q000633:toxicity*; D008252:Macaca fascicularis; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons; D010446:Peptide Fragments / Q000032:analysis
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007136:Immunoglobulins; D010446:Peptide Fragments; C090698:SP1 antigen; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D007854:Lead; D053829:Amyloid Precursor Protein Secretases