TY - JOUR
T1 - Alzheimer's Disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb)
T2 - Evidence for a developmental origin and environmental link for AD
AU - Wu, Jinfang
AU - Basha, Md Riyaz
AU - Brock, Brian
AU - Cox, David P.
AU - Cardozo-Pelaez, Fernando
AU - McPherson, Christopher A.
AU - Harry, Jean
AU - Rice, Deborah C.
AU - Maloney, Bryan
AU - Chen, Demao
AU - Lahiri, Debomoy K.
AU - Zawia, Nasser H.
PY - 2008/1/2
Y1 - 2008/1/2
N2 - 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 β-amyloid (Aβ) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (β-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 Aβ 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.
AB - 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 β-amyloid (Aβ) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (β-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 Aβ 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.
KW - Amyloidogenesis
KW - Development
KW - Environmental exposure
KW - Epigenetic regulation
KW - Pb
KW - Transcription factor
UR - http://www.scopus.com/inward/record.url?scp=38149024924&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4405-07.2008
DO - 10.1523/JNEUROSCI.4405-07.2008
M3 - Article
C2 - 18171917
AN - SCOPUS:38149024924
SN - 0270-6474
VL - 28
SP - 3
EP - 9
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 1
ER -