The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease

Regulation of intracellular free arachidonic acid in Aplysia nervous system

We have studied the regulation of arachidonic acid (AA) uptake, metabolism, and release in Aplysia nervous system. Following uptake of [ 3 H]AA, the distribution of radioactivity in intracellular and extracellular lipid pools was measured as a function of time in the presence or absence of exogenous AA. The greatest amount of AA was esterified into phosphatidylinositol (relative to pool size). We found that the intracellular free AA pool underwent rapid turnover, and that radioactive free AA and eicosanoids were released at a rapid rate into the extracellular medium, both in the presence and absence of exogenous AA. Most of the released radioactivity originated from phosphatidylinositol.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48020/1/232_2005_Article_BF01868464.pd