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Neurobiol Dis. 2019 Mar 15;127:449-461. doi: 10.1016/j.nbd.2019.03.009. [Epub ahead of print]

Reciprocal modulation between amyloid precursor protein and synaptic membrane cholesterol revealed by live cell imaging.

Author information

1
Department of Pharmacology, Vanderbilt University, United States of America.
2
Department of Cell and Developmental Biology, Vanderbilt University, United States of America.
3
Department of Biochemistry, Vanderbilt University, United States of America.
4
Department of Biochemistry, Vanderbilt University, United States of America; Department of Medicine, Vanderbilt University Medical Center, United States of America.
5
Department of Pharmacology, Vanderbilt University, United States of America; Brain Institute, Florida Atlantic University, United States of America. Electronic address: zhangq@health.fau.edu.

Abstract

The amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimer's disease (AD). However, APP distribution across different subcellular membrane compartments and its function in neurons remains unclear. 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 and used it to measure APP's distribution, subcellular trafficking, and cleavage in live neurons. This reporter, closely resembling endogenous APP, revealed only a limited correlation between synaptic activities and APP trafficking. However, the synaptic surface fraction of APP was increased by a reduction in membrane cholesterol levels, a phenomenon that involves APP's cholesterol-binding motif. Mutations at or near binding sites not only reduced both the surface fraction of APP and membrane cholesterol levels in a dominant negative manner, but also increased synaptic vulnerability to moderate membrane cholesterol reduction. Our results reveal reciprocal modulation of APP and membrane cholesterol levels at synaptic boutons.

KEYWORDS:

Amyloid precursor protein; Cholesterol; Membrane; Proteolysis; Synapse; Trafficking

PMID:
30885793
DOI:
10.1016/j.nbd.2019.03.009

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