Saturday, February 13, 2010

Inflammation and Alzheimers

For a long time it was believed that inflammation played a critical role in the development of Alzheimer's. This can be true but needs to be carefully qualified because as the below abstract demonstrates "massive gliosis" induced by interleukin 6 actually prevented amyloid deposition. Look at the gliosis link for the wikipedia entry, it is a good example of when not to trust Wiki. Wiki is very useful for a quick overview of relatively mundane and simple concepts but can be very misleading when dealing with cutting edge research. In the abstract overleaf the bods found that inducing gliosis, which is typically associated with inflammation, is actually leading to clearance of amyloid. Clearance of amyloid is the great interest in current Alzheimer's research and this for the simple reason that amyloid aggregation appears to be a key driving factor in Alzheimer's disease. As usual, with more research, what once looked obvious becomes blurred. Inflammation is found in many pathologies but it is a mistake to assume that inflammation is the cause of that pathology. As this study indicates it can play a vital protective role.

(The FASEB Journal. 2010;24:548-559.)

Massive gliosis induced by interleukin-6 suppresses Aß deposition in vivo: evidence against inflammation as a driving force for amyloid deposition

Proinflammatory stimuli, after amyloid ß (Aß) deposition, have been hypothesized to create a self-reinforcing positive feedback loop that increases amyloidogenic processing of the Aß precursor protein (APP), promoting further Aß accumulation and neuroinflammation in Alzheimer’s disease (AD). Interleukin-6 (IL-6), a proinflammatory cytokine, has been shown to be increased in AD patients implying a pathological interaction. To assess the effects of IL-6 on Aß deposition and APP processing in vivo, we overexpressed murine IL-6 (mIL-6) in the brains of APP transgenic TgCRND8 and TG2576 mice. mIL-6 expression resulted in extensive gliosis and concurrently attenuated Aß deposition in TgCRND8 mouse brains. This was accompanied by up-regulation of glial phagocytic markers in vivo and resulted in enhanced microglia-mediated phagocytosis of Aß aggregates in vitro. Further, mIL-6-induced neuroinflammation had no effect on APP processing in TgCRND8 and had no effect on APP processing or steady-state levels of Aß in young Tg2576 mice. These results indicate that mIL-6-mediated reactive gliosis may be beneficial early in the disease process by potentially enhancing Aß plaque clearance rather than mediating a neurotoxic feedback loop that exacerbates amyloid pathology. This is the first study that methodically dissects the contribution of mIL-6 with regard to its potential role in modulating Aß deposition in vivo.—Chakrabarty, P., Jansen-West, K., Beccard, A., Ceballos-Diaz, C., Levites, Y., Verbeeck, C., Zubair, A. C., Dickson, D., Golde, T. E., Das, P. Massive gliosis induced by interleukin-6 suppresses Aß deposition in vivo: evidence against inflammation as a driving force for amyloid deposition.
Key Words: Alzheimer’s disease • neuroinflammation • APP • recombinant adeno-associated virus

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