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Differential regulation of the high‐affinity choline transporter by wild‐type and Swedish mutant amyloid precursor protein
Author(s) -
Cuddy Leah K.,
Seah Claudia,
Pasternak Stephen H.,
Rylett Rebecca Jane
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13167
Subject(s) - endocytosis , endosome , cholinergic , microbiology and biotechnology , amyloid precursor protein , acetylcholine , chemistry , choline , cholinergic neuron , internalization , mutant , biochemistry , cell , biology , endocrinology , medicine , alzheimer's disease , disease , gene
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 βCTF 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 βCTF fragment or by Aβ released from cells.High‐affinity choline transporter (CHT) takes choline into cholinergic neurons for acetylcholine synthesis. Amyloid precursor protein (APP) interacts with CHT proteins, but this is decreased for Swedish mutant APP (APP Swe ). CHT cell surface levels and localization to early endosomes, and choline uptake activity are changed similarly by APP wt or APP Swe . APP Swe mediates effects indirectly potentially by βCTF or Aβ.