Mechanisms of nitrosamine-mediated neurodegeneration: potential relevance to sporadic Alzheimer's disease.
Streptozotocin (STZ) is a nitrosamine-related compound that causes Alzheimer's disease (AD)-type neurodegeneration with cognitive impairment, brain insulin resistance, and brain insulin deficiency. Nitrosamines and STZ mediate their adverse effects by causing DNA damage, oxidative stress, lipid peroxidation, pro-inflammatory cytokine activation, and cell death, all of which occur in AD. We tested the hypothesis that exposure to N-nitrosodiethylamine (NDEA), which is widely present in processed/preserved foods, causes AD-type molecular and biochemical abnormalities in central nervous system (CNS) neurons. NDEA treatment of cultured post-mitotic rat CNS neurons (48 h) produced dose-dependent impairments in ATP production and mitochondrial function, and increased levels of 8-hydroxy-2'-deoxyguanosine, 4-hydroxy-2-nonenal, phospho-tau, amyloid-beta protein precursor-amyloid-beta (A beta PP-A beta), and ubiquitin immunoreactivity. These effects were associated with decreased expression of insulin, insulin-like growth factor (IGF)-I, and IGF-II receptors, and choline acetyltransferase. Nitrosamine exposure causes neurodegeneration with a number of molecular and biochemical features of AD including impairments in energy metabolism, insulin/IGF signaling mechanisms, and acetylcholine homeostasis, together with increased levels of oxidative stress, DNA damage, and A beta PP-A beta immunoreactivity. These results suggest that environmental exposures and food contaminants may play critical roles in the pathogenesis of sporadic AD.
de la Monte
Suzanne M
SM
Department of Pathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. SuzanneDeLaMonte MD@Brown.edu
Tong
Ming
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002525:Cerebellar Cortex / Q000166:cytology; D002795:Choline O-Acetyltransferase; D004249:DNA Damage / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004052:Diethylnitrosamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I; D008928:Mitochondria / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017527:Receptor, IGF Type 2; D013311:Streptozocin / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D017527:Receptor, IGF Type 2; D025801:Ubiquitin; D004052:Diethylnitrosamine; D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000255:Adenosine Triphosphate; D002795:Choline O-Acetyltransferase; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal