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 agai nst beta-amyloid (A beta) toxicity in neurons. We investigated the effects of A beta (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 muM AP (1-40), microglia from embryonic and old rats increase TNF secretion, although microglia from middle-age rats did not pro duce detectable levels of TNF, When low concentrations of TNF are added to neurons together with A beta (1-40) in the absence of exogenous antioxidant s, neuroprotection for old neurons is significantly less than neuroprotecti on for middle-age neurons. In neurons from old rats, high levels of TNF tog ether with A beta are more toxic than in neurons from middle-age or embryon ic rats. These results are discussed in relation to neuroprotection and tox icity of the age-related pathology of AD. (C) 2001 Wiley-Liss, Inc.