Conference Index | Round Tables | Selected Abstracts | News Summaries

Neuroinflammation Roundtable

by Walter J. Lukiw

July 21, 1998 Session chair C.E. Finch began with an overview of the involvement of inflammatory mechanisms in AD, pointing out that as early as 1907 Alzheimer himself described the gliosis in AD brains. It was not until 1964 (>57 years later!!) that R.D. Terry described that microglia in senile plaques seemed to be the actual sources of amyloid. Further evidence has accumulated since 1980: C1q in senile plaques (Eikelenboom, 1982); many other C-proteins in plaques (Griffin and McGeers, 1989); C-mRNAs in neurons/glia (Finch, 1991, 1992); first clinical trial of NSAID in AD (Rogers 1993); C1q in CSF and Cognitive impairment (Cotman, 1994); and "aging renders the brain vulnerable to beta-amyloid neurotoxicity" (Yankner et al., 1998).

At this meeting, P. Eikelenboom (abstract 941) noted that brain inflammation may play an important role in dementia, delirium and neurodegeneration. Beta-amyloid deposits are associated with inflammatory proteins and C1q, the first complement factor, as well as C4, C3, C4 binding protein, vitronectin, ApoE, ICAM, a1 antichymotrypsin and other acute phase proteins. In addition, neurofibrillary tangles are associated with activated microglia, cytokines, complement activation and acute phase response proteins (with no apparent involvement of IgG, T and B lymphocytes), as well as upregulation of ICAM, VCAM and E-selectin in a local acute inflammatory response. What's more, IL-1 and IL-6 both stimulate APP production, which could promote fibrillar BA deposition, leading to further neurodegeneration and inflammatory response, triggering still more APP production, thereby setting a positive feedback cycle into motion.

J. Rogers et al. (abstract 942) argued that the stressed CNS is exquisitely sensitive to inflammation, and that the brain's inflammatory response is distinct from that seen in other systems. He described markers of inflammation in AD neuropathology and influences of resident inflammatory pathways and mechanisms at the molecular level. C1q, a protein occurring early in the complement cascade (and found to bind beta amyloid) may be one of the most potent promoters of A-beta aggregation. C1q, scavenger cells, oxygen free radicals and cytokine induction all have deleterious effects on nerve cells, and what's more, appear to be tightly coupled in the positive feedback pathway, with each player interacting with the other to exacerbate A-beta-based neuroinflammation. Rogers also presented evidence that C1q has a linear association with NFTs, and may be involved in a similar positive feedback cycle in the generation of NFTs.

Numerous pharacological agents are now under development, and some are in clinical trials, to intervene in the neuroinflammatory cycle. In addition to NSAIDS, other drugs may be useful, including COX inhibitors, hydroxychloroquine, glucocorticoids and colchicines. P. Aisen et al. (abstract 944) outlined a just-completed AD clinical trial of the steroid drug prednisone, a potent anti-inflammatory with marginal adverse effects. Another way to circumvent side effects will be to develop treatments based on selective inhibitors of cyclo-oxygenase 2 (COX-2), which mediates inflammation but not gastric function (mediated by COX-1). COX-2 is prominent in neurons of of the cortex and hippocampus and is primary target for new drug compounds now in development by Searle (the workshop sponsor) and other pharmaceutical companies.

Novel therapies may emerge from research on the NFk-B-related family of proteins, which are transcription factors involved in stress and immune responses. NFk-B is activated by UV radiation, by glutamate, and by oxygen free radicals. What's more, NFk-B may be involved in APP and cyclooxygenase transcription. Meno et al. (abstract 945) reported that the APP promoter contains two NFkB binding sites (5'-GGGGTTTCAC-3') -2500 and -1500 bp relative to the transcription start at +1, suggesting that NFkB may play a role in the regulation of APP transcription. The APP gene promoter also has two sites (at -330 and -90 bp) for AP1, another signalling molecule involved in inflammatory gene expression. NFkB also appears to mediate the ability of IL-1b and glutamate to activate transcription of APP in transfected SH5Y5 cells, and increases in APP mRNA were correlated with increases in NF-kB-DNA binding. Because NF-kB is multiply involved in processes that may be contributing to AD, it is a tempting target for drug development. Promising compounds already exist: aspirin and sodium salicylate, for example, inhibit NF-kB-DNA binding.