Molecular and cellular mediators of Alzheimer's disease inflammation.

A wide range of inflammatory mediators has been demonstrated in the Alzheimer’s disease (AD) brain during the past 15 years (for previous reviews, see [6, 279,298,340,343]). Questions nonetheless remain, including even the designation of AD inflammatory mechanisms as a true inflammatory response. Like multiple sclerosis, the cardinal signs of peripheral inflammation, the “rubor et tumor cum calore et dolore” (redness and swelling with heat and pain) that Cornelius Celsus defined as criteria 2000 years ago, are not present in AD. Indeed, AD inflammation does not appear to include even cell-mediated humoral lymphocyte responses, as multiple sclerosis clearly does. Rather, our current understanding of AD inflammation suggests that it is an endogenously-mediated, localized reaction, an innate inflammatory response similar to that mounted in the periphery when localized tissue damage and the chronic deposition of highly insoluble, abnormal material occurs. Such primarily macrophagemediated reactions have been classed as inflammatory for over a century, and that designation, with glia as the brain intermediaries, certainly should hold for AD. Henry Wisniewski, who we honor by this special journal issue, was one of the first to come to grips with these simple principles of AD inflammation, and to apply them to other brain disorders. If we understand that localized brain inflammation is likely to arise wherever there is localized brain damage and deposits of highly insoluble, abnormal material, then prion diseases be-