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Cell Rep. 2014 Jun 12;7(5):1560-1576. doi: 10.1016/j.celrep.2014.04.024. Epub 2014 May 15.

APP homodimers transduce an amyloid-β-mediated increase in release probability at excitatory synapses.

Author information

1
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
2
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
3
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
4
Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Republic of Ireland; Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115, USA.
5
Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115, USA.
6
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
7
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel. Electronic address: islutsky@post.tau.ac.il.

Abstract

Accumulation of amyloid-β peptides (Aβ), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer's disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aβ40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aβ40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aβ40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer's disease.

PMID:
24835997
DOI:
10.1016/j.celrep.2014.04.024
[Indexed for MEDLINE]
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