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Neuroinflammation, spent protein transport, and autophagy/proteostatic failure

Neuroinflammation, spent protein transport, and autophagy/proteostatic failure . Neuronal stresses elicited by untoward genetics, trauma, and aging are associated with elevated levels of the neuronal acute phase protein APP and release of sAPP.

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Neuroinflammation, spent protein transport, and autophagy/proteostatic failure

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  1. Neuroinflammation, spent protein transport, and autophagy/proteostatic failure • Neuronal stresses elicited by untoward genetics, trauma, and aging are associated with elevated levels of the neuronal acute phase protein APP and release of sAPP. • sAPP activates glia and induces their expression of interleukin-1β, which in turn induces excess expression of APP in neurons, creating a self-amplifying cycle that perpetuates neuronal stress. • As APP expression increases with advancing age, there is a corresponding increase in the expression of the anterograde motor protein dynein. • In Alzheimer’s, there is a failure in transport that results in formation of aggregates that contain not only APP but also hyperphosphorylated tau, α-synuclein, and Parkin. • Such changes may be applicable to other diseases characterized by neuronal stress, glial activation, transport proteostatic failure.

  2. Neuroinflammation, spent protein transport, and autophagy/proteostatic failure Treatment of cultured human NT2 neurons with IL-1β increases protein levels of ubiquitin ligase E3 (Parkin), suggesting that in human neurons glia-derived neuroinflammatory cytokine IL-1 overexpression and failures in anterograde transport and protein degradation pathways are linked.

  3. APP transgenic mouse model of Alzheimer’s responds to Ibuprofen treatment by decreasing IL-1β Lim et al., J. Neurosci., August 1, 2000, 20(15):5709–5714

  4. VA Data on Alzheimer risk with Ibuprofen or Naproxen Vlad et al Neurology, 2008 May 6;70(19):1672-7

  5. I wonder??? Why, based on findings of the VA’s own researchers, isn’t the VA recommending or at least exploring the prophylactic use of ibuprofen as a preventative strategy toward forestalling onset of Alzheimer’s?

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