Age‐ and concentration‐dependent neuroprotection and toxicity by TNF in cortical neurons from β‐amyloid

Abstract

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.

Microglia enhance β‐amyloid peptide‐induced toxicity in cortical and mesencephalic neurons by producing reactive oxygen species

“…Treatment of mesencephalic or cortical neuron-glia cultures with the same concentrations of Ab for 72 h did not produce detectable levels of NO, TNF-a and IL-1b. The lack of effect of Ab on the production of NO, TNF-a and IL-1b in our study is different from published reports (Ii et al 1996;Viel et al 2001). The difference is Fig.…”

“…With higher concentrations of Ab (10 lM), significant amounts of NO and TNF-a were detected in our neuron-glia cultures (data not shown) as described in other reports (Ii et al 1996;Viel et al 2001). Taken together, the inhibition of microglia-generated superoxide might be the most efficient way to protect neurons from damage by Ab.…”

“…It has been reported that free radicals are generated in dopaminergic neurons by the oxidation of DA via monoamine oxidase (Olanow 1992). The explanations for AD should take into account the fact that age is the primary risk factor for the disease (Viel et al 2001). One important factor associated with aging is the accumulation of oxidative damage caused by free radicals (Ames et al 1993;Lees 1993).…”

β-Amyloid-Stimulated Microglia Induce Neuron Death via Synergistic Stimulation of Tumor Necrosis Factor α and NMDA Receptors

“…Although we propose a role for TNF␣ potentiation of NMDA receptor-dependent death, previous studies have characterized an ability of TNF␣ to provide neuroprotection (Barger et al, 1995;Houzen et al, 1997;Mattson et al, 1997;Carlson et al, 1999;Kaltschmidt et al, 1999;Keller et al, 1999;Glazner et al, 2000;Diem et al, 2001;Viel et al, 2001;Bruce-Marchetti et al, 2004). Importantly, some of these neuroprotective paradigms have demonstrated TNF␣ protection against NMDA-mediated death in apparent contrast to our findings (Houzen et al, 1997;Furukawa and Mattson, 1998).…”

Role of Microglia in Inflammatory Process in Parkinson’s Disease

“…Aging is speculated to promote a change from the protective to the toxic phenotype of activated microglia, as in the toxic change in microglia hypothesized by Sawada M. et al (2006). Cultures of amyloid β-peptide (Aβ)-stimulated microglia from aged rats were reported to show more evidence of toxicity than those from middle-aged or embryonic mice (Viel et al, 2001). Furthermore, MPTP neurotoxicity is greater in aged mice than in young mice, and is accompanied by agerelated microglial activation (Sugama et al, 2003).…”