Differential regulation of the high-affinity choline transporter by wild-type and Swedish mutant amyloid precursor protein

作者：Cuddy Leah K; Seah Claudia; Pasternak Stephen H; Rylett Rebecca Jane^*

来源：Journal of Neurochemistry, 2015, 134(4): 769-782.

DOI：10.1111/jnc.13167

• Alzheimer's disease
• cholinergic
• protein interactions
• protein trafficking
• -amyloid

The high-affinity choline transporter (CHT) is responsible for choline uptake into cholinergic neurons, with this being the rate-limiting step for acetylcholine production. Altering CHT protein disposition directly impacts choline uptake activity and cholinergic neurotransmission. Amyloid precursor protein (APP) interacts with CHT proteins and increases their endocytosis from the cell surface. The goal of this study was to examine regulation of CHT trafficking and activity by wild-type APP (APP(wt)) and determine if this differs with Swedish mutant APP (APP(Swe)) in SH-SY5Y human neuroblastoma cells. APP(Swe) differs from APP(wt) in its trafficking from the cell surface through endosomes. We report for the first time that CHT interacts significantly less with APP(Swe) than with APP(wt). Surprisingly, however, CHT cell surface levels and choline uptake activity are decreased to the same extent and CHT co-localization to early endosomes increased similarly in cells expressing either APP(wt) or APP(Swe). A critical observation is that CHT co-immunoprecipitates with CTF from APP(Swe)-expressing cells. We propose that decreased CHT function is mediated differently by APP(wt) and APP(Swe); APP(wt) interaction with CHT facilitates its endocytosis from the cell surface, whereas the effect of APP(Swe) on CHT is mediated indirectly potentially by binding to the CTF fragment or by A released from cells.

• 出版日期2015-8