Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 17, Issue 4, Pages 817-825Publisher
IOS PRESS
DOI: 10.3233/JAD-2009-1098
Keywords
Alzheimer's disease; diabetes mellitus; environmental toxin; neurodegeneration; nitrosamine
Categories
Funding
- National Institutes of Health [AA-02666, AA-02169, AA-11431, AA-12908, K24-AA-16126]
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R37AA011431, R01AA011431, R01AA002666, R01AA012908, R56AA011431, K24AA016126, R37AA002666] Funding Source: NIH RePORTER
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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.
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