title: Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia.
abstract: The local pattern of proinflammatory cytokine release was studied in Alzheimer disease (AD) and vascular dementia (VAD), by measuring intrathecal levels of IL-1 beta, IL-6, TNF-alpha, and its naturally occurring antagonists, soluble TNF receptors I and II. The cytokine levels were related to neuronal damage, as measured by the intrathecal tau concentration, to cerebral apoptosis assessed by levels of Fas/APO-1 and bcl-2, and to clinical variables. In vitro analysis was performed to study the effect of TNF-alpha on the production of bcl-2, an antiapoptotic factor, by human neuronal cells. Patients with both AD and VAD displayed significantly higher intrathecal levels of TNF-alpha compared to controls. In addition, patients with AD showed significantly negative correlations between the intrathecal levels of TNF-alpha and the levels of Fas/APO-1 as well as of tau protein. The level of bcl-2 in supernatants of TNF-alpha-exposed cultures of human neuronal cells was up to three times higher than in control supernatants. Our study demonstrates intrathecal production of TNF-alpha in patients with dementias, suggesting that this cytokine may have a neuroprotective role in these neurodegenerative conditions as evidenced by negative correlations between this cytokine and (i) levels of intrathecal Fas/APO-1 and (ii) levels of tau protein, both parameters closely related to brain damage. Our in vitro data suggest that TNF-alpha exerts its neuroprotective effect by stimulating neuronal cells to express bcl-2, a molecule which downregulates apoptosis.
authors.affiliation: Department of Rheumatology, University of Göteborg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Tarkowski
authors.forename: K
authors.initials: K
authors.lastname: Blennow
authors.forename: A
authors.initials: A
authors.lastname: Wallin
authors.forename: A
authors.initials: A
authors.lastname: Tarkowski
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D015140:Dementia, Vascular / Q000378:metabolism*; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000097:blood / Q000134:cerebrospinal fluid; D015850:Interleukin-6 / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000134:cerebrospinal fluid*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000134:cerebrospinal fluid; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000134:cerebrospinal fluid*; D019014:fas Receptor / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D007375:Interleukin-1; D015850:Interleukin-6; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016875:tau Proteins