Affiliations: Departments of Pathology, Clinical Neuroscience, and Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
Correspondence:
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Corresponding author: Dr. Suzanne M. de la Monte, MD, MPH, Pierre Galletti Research Building, Rhode Island Hospital, 55 Claverick Street, Room 419, Providence, Rhode Island 02903, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: [email protected].
Note: [] Communicated by Paula Moreira
Abstract: 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-β protein precursor-amyloid-β (AβPP-Aβ), 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 AβPP-Aβ immunoreactivity. These results suggest that environmental exposures and food contaminants may play critical roles in the pathogenesis of sporadic AD.
