Reciprocal Modulation Between Amyloid Precursor Protein and Synaptic Membrane Cholesterol Revealed By Live Cell Imaging
The amyloid precursor protein (APP) has been extensively studied because of its relevance to Alzheimer's disease (AD). However, its membrane distribution and neuronal function remain unclear. Here, we generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain to measure surface and intracellular APP distributions and its cleavage events. This fusion protein, closely resembling endogenous APP, demonstrated a limited correlation between synaptic activities and APP trafficking at synapses and neurites. Inhibition of the three major secretases distinctly affected membrane APP distribution. Intriguingly, the surface APP was inversely correlated to membrane cholesterol, a phenomenon involving APP's cholesterol-binding motif. A point mutation within this motif not only increased surface APP but also caused synaptic swelling when membrane cholesterol was reduced. Our results reveal previously unappreciated relationships between APP trafficking and processing and between membrane APP and cholesterol homeostasis at synapses.
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