Age- and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from beta-amyloid.
The induction of an inflammatory response and release of cytokines such as TNF may be involved in the age-related etiology of Alzheimer disease (AD). In the brain, microglia have been shown to produce a wide variety of immune mediators, including the pro-inflammatory cytokine tumor necrosis factor (TNF). We hypothesize that with age there is increased ability of microglia to produce TNF or that age decreases the neuroprotective effect of TNF against beta-amyloid (Abeta) toxicity in neurons. We investigated the effects of Abeta(1-40) on TNF secretion from forebrain cultures of microglia from embryonic, middle-age (9-month) and old (36-month) rats. Over the first 12 hr of exposure to 10 microM Abeta (1-40), microglia from embryonic and old rats increase TNF secretion, although microglia from middle-age rats did not produce detectable levels of TNF. When low concentrations of TNF are added to neurons together with Abeta (1-40) in the absence of exogenous antioxidants, neuroprotection for old neurons is significantly less than neuroprotection for middle-age neurons. In neurons from old rats, high levels of TNF together with Abeta are more toxic than in neurons from middle-age or embryonic rats. These results are discussed in relation to neuroprotection and toxicity of the age-related pathology of AD.
Viel
J J
JJ
Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62794-9626, USA.
McManus
D Q
DQ
Smith
S S
SS
Brewer
G J
GJ
D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D051926:Basigin; D001798:Blood Proteins; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005333:Fetus; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D030161:Avian Proteins; D001798:Blood Proteins; C102624:Bsg protein, Gallus gallus; C079432:Bsg protein, rat; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C078592:amyloid beta-protein (1-40); D051926:Basigin; D010751:Phosphopyruvate Hydratase