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

Leah Katherine Cuddy, Claudia Seah, Stephen H. Pasternak, Rebecca Jane Rylett*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

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 (APPwt) and determine if this differs with Swedish mutant APP (APPSwe) in SH-SY5Y human neuroblastoma cells. APPSwe differs from APPwt in its trafficking from the cell surface through endosomes. We report for the first time that CHT interacts significantly less with APPSwe than with APPwt. 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 APPwt or APPSwe. A critical observation is that CHT co-immunoprecipitates with βCTF from APPSwe-expressing cells. We propose that decreased CHT function is mediated differently by APPwt and APPSwe; APPwt interaction with CHT facilitates its endocytosis from the cell surface, whereas the effect of APPSwe on CHT is mediated indirectly potentially by binding to the βCTF fragment or by Aβ released from cells.

Original languageEnglish (US)
Pages (from-to)769-782
Number of pages14
JournalJournal of neurochemistry
Volume134
Issue number4
DOIs
StatePublished - Aug 1 2015

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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