neuroinflammation, spent protein transport, and autophagy/proteostatic failure
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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. - PowerPoint PPT PresentationTRANSCRIPT
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.
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.
Neuroinflammation, spent protein transport, and autophagy/proteostatic failure
Lim et al., J. Neurosci., August 1, 2000, 20(15):5709–5714
APP transgenic mouse model of Alzheimer’s responds to Ibuprofen treatment by decreasing IL-1β
VA Data on Alzheimer risk with Ibuprofen or Naproxen
Vlad et al Neurology, 2008 May 6;70(19):1672-7
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?
I wonder???