APP homodimers transduce an amyloid-β-mediated increase in release probability at excitatory synapses.
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.
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Hilla
H
Fogel
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Samuel
S
Frere
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Oshik
O
Segev
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
Shashank
S
Bharill
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Ilana
I
Shapira
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.
Neta
N
Gazit
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.
Tiernan
T
O'Malley
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Edden
E
Slomowitz
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel.
Yevgeny
Y
Berdichevsky
Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham & Women's Hospital, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Dominic M
DM
Walsh
Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
Ehud Y
EY
Isacoff
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Joel A
JA
Hirsch
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.
Inna
I
Slutsky
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005089:Exocytosis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000502:physiology; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission; D013572:Synaptic Vesicles / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D002118:Calcium