Mint-dependent regulation of amyloid precursor protein trafficking and processing in neurons

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting from dysfunction and death of neurons leading to dementia and ultimately fatality. AD is hallmarked by the deposition of extracellular plaques composed of aggregates of small, insoluble amyloid-beta (Abeta) peptides. Abeta is generated by sequential beta- and gamma-secretase-mediated cleavage of the amyloid precursor protein (APP). APP is a type-1 transmembrane protein with a large extracellular domain and small intracellular domain containing a conserved endocytosis motif. Endocytosis and intracellular trafficking of APP are critical steps in Abeta generation due to favorable conditions for enzyme activity within the compartments of the endosomal pathway. The endocytosis motif of APP can bind to adaptor proteins containing a phosphotyrosine-binding (PTB) domain that is involved in Abeta generation. Mints (Munc-18 interacting proteins) are a three-member family of multi-domain adaptor proteins comprised of the neuron-specific Mints 1 and 2 and the ubiquitously expressed Mint 3. Mints have been shown to bind directly to APP and alter APP processing. However, the underlying cellular mechanism of Mint-dependent regulation on APP trafficking has yet to be fully elucidated. Therefore, I investigated the function of Mints in APP trafficking and the regulation of the post-internalized fate of APP and processing events. We demonstrate that phosphorylation of Mint2 by the tyrosine kinase Src regulates the APP endocytic sorting pathway resulting in altered Abeta secretion. In addition, because neuronal activity has been shown to regulate APP processing, I examined the role of Mints in activity-dependent APP trafficking and processing. I conclude that Mint proteins are required for neuronal activity-dependent APP endocytosis and insertion back to the plasma membrane in neurons. These studies are the first steps in gaining cellular and molecular insight into how Mints regulate activity-induced APP internalization and how APP is sorted along the endocytotic pathways in regulating Abeta generation.