The presence of tangles of abnormally phosphorylated tau is a characteristic of Alzheimer's disease (AD), and the loss of synapses correlates with the degree of dementia. In addition, the overexpression of interleukin-1 (IL-1) has been implicated in tangle formation in AD. As a direct test of the requirement for IL-1 in tau phosphorylation and synaptophysin expression, IL-1 actions in neuron-microglia cocultures were manipulated. Activation of microglia with secreted beta-amyloid precursor protein or lipopolysaccharide elevated their expression of IL-1alpha, IL-1beta, and tumor necrosis factor alpha (TNFalpha) mRNA. When such activated microglia were placed in coculture with primary neocortical neurons, a significant increase in the phosphorylation of neuronal tau was accompanied by a decline in synaptophysin levels. Similar effects were evoked by treatment of neurons with recombinant IL-1beta. IL-1 receptor antagonist (IL-1ra) as well as anti-IL-1beta antibody attenuated the influence of activated microglia on neuronal tau and synaptophysin, but anti-TNFalpha antibody was ineffective. Some effects of microglial activation on neurons appear to be mediated by activation of p38 mitogen-activated protein kinase (p38-MAPK), because activated microglia stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of p38-MAPK reversed the influence of IL-1beta on tau phosphorylation and synaptophysin levels. Our results, together with previous observations, suggest that activated microglia may contribute to neurofibrillary pathology in AD through their production of IL-1, activation of neuronal p38-MAPK, and resultant changes in neuronal cytoskeletal and synaptic elements.

Neurotoxic microglial-neuronal interactions have been implicated in the pathogenesis of various neurodegenerative diseases such as Alzheimer's disease, and vitamin E has been shown to have direct neuroprotective effects. To determine whether vitamin E also has indirect neuroprotective effects through suppression of microglial activation, we used a microglial-neuronal coculture. Lipopolysaccharide (LPS) treatment of a microglial cell line (N9) induced a time-dependent activation of both p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-κB (NFκB), with consequent increases in interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production. Differentiated neuronal cells (PC12 cells treated with nerve growth factor) exhibited marked loss of processes and decreased survival when cocultured with LPS-activated microglia. Preincubation of microglia with vitamin E diminished this neurotoxic effect, independently of direct effects of the antioxidant on the neuronal cells. Microglial NO production and the induction of IL-1α and TNFα expression also were attenuated by vitamin E. Such antiinflammatory effects of vitamin E were correlated with suppression of p38 MAPK and NFκB activation and were mimicked by an inhibition of either p38 MAPK (by SB203580) or NFκB (by decoy oligonucleotides). These results suggest that, in addition to the beneficial effects of providing direct antioxidant protection to neurons reported by others, vitamin E may provide neuroprotection in vivo through suppression of signaling events necessary for microglial activation. KeywordsAlzheimer's disease; interleukin-1; NFκB; nitric oxide; p38 mitogen-activated protein kinase; tumor necrosis factor; vitamin E Brain responses to injury include activation of glia (microglia and astrocytes) and consequent release of proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), and other glia-derived factors, such as nitric oxide (NO). A synergistic neurotoxic effect of IL-1 and TNF-α has been shown in mixed glial-neuronal Jeohn et al., 1998), and these potentially neurotoxic effects may, in turn, aggravate further neuronal injury (Dawson et al., 1991;Chao et al., 1992). Evidence is accumulating that activated microglia contribute to the neuropathological changes in Alzheimer's disease (AD) through overexpression of IL-1 (Griffin et al., 1989Mrak and Griffin, 2000). A direct effect of microglia-derived IL-1 has been demonstrated in the acetylcholine system, where IL-1 directly induces acetylcholine esterase expression and activity (Li et al., 2000b). Microglia activation has also been suggested to have effects on other neurotransmitter systems, such as glutamate (Barger and Basile, 2001), γ-aminobutyric acid (Scali et al., 1999), and serotonin (Tsai and McNulty, 1997). These studies suggest that understanding glial-neuronal interactions and mechanisms involved in regulation of microglial activation are important steps toward identification of therapeutic targets and potential d...

Si 00~3has been implicated in the formation of dystrophic neurites, overexpressing /3-amyloid precursor protein (/3APP), in the~3-amyloid plaques of Alzheimer's disease. We assessed the effects of Si 00/3 on cell viability of, neurite outgrowth from, and /3APP expression by neurons in primary cultures from fetal rat cortex. Si 00~3 (1-10 ng/ml) enhanced neuronal viability (as assessed by increased mitrochondrial activity and decreased lactic acid dehydrogenase release) and promoted neurite outgrowth. Higher levels of S100j3 (100 ng/ml, but not 1 gIml) produced qualitatively similar, but less marked,

Background: Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is now well recognized. Such cases of concurrent AD and Lewy body disease (AD/ LBD) show neuropathological changes that include Lewy bodies (α-synuclein aggregates), neuritic amyloid plaques, and neurofibrillary tangles (hyperphosphorylated tau aggregates). The cooccurrence of these clinical and neuropathological changes suggests shared pathogenic mechanisms in these diseases, previously assumed to be distinct. Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD.

Both the astrocytic cytokine S100B and the pro-inflammatory interleukin-1 (IL-1) are elevated in Alzheimer's disease, and each has been implicated in Alzheimer-related neuropathology. We examined the gene-regulatory events through which S100B induces IL-1b expression. In primary microglia, S100B activated the transcription factors Sp1 and NFjB, followed by an increase in IL-1b mRNA levels. The latter was blocked by a peptide inhibitor of NFjB or by a double-stranded oligonucleotide containing a NFjB-binding site to serve as 'decoy' DNA and reduce available NFjB. But in primary cortical neurons, decoy and siRNA experiments indicated that the IL-1b induction by S100B was mediated by Sp1 without evidence of a role for NFjB. Our results suggest that the elevation of S100B and IL-1 in Alzheimer brain and consequent neurodegenerative events are mediated through cell-type specific gene-regulatory events, providing mechanistic insight into connections between glial activation and neuronal dysfunction.