@article{93cdf1061c7649f788fecc08960db8dd,
title = "APP homodimers transduce an amyloid-β-mediated increase in release probability at excitatory synapses",
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.",
author = "Hilla Fogel and Samuel Frere and Oshik Segev and Shashank Bharill and Ilana Shapira and Neta Gazit and Tiernan O'Malley and Edden Slomowitz and Yevgeny Berdichevsky and Walsh, {Dominic M.} and Isacoff, {Ehud Y.} and Hirsch, {Joel A.} and Inna Slutsky",
note = "Funding Information: We thank Dr. Gerd Multhaup for the comments on the manuscript, Dr. Avraham Yaron for advice on the Aβ40-biotin binding assay, Dr. Ruth Gabizon for providing PrP C knockout mice, and all the lab members for help and discussions. This work was supported by a European Research Council starting grant (281403, I. Slutsky), the Legacy Heritage Biomedical Program of the Israel Science Foundation (865/11, to I. Slutsky), the Alzheimer{\textquoteright}s Association (NIRG-10-172308, to I. Slutsky), the Israel Science Foundation (993/08, 170/08, and 398/13, to I. Slutsky), Marie Curie CIG grant 33458 (to S.F.), the Foundation for Neurologic Diseases (DMW), NIH grant R01 NS35549 (to E.Y.I.), and by a Deutsche Israel Programme grant (to J.A.H.). I. Slutsky is grateful to Sheila and Denis Cohen Charitable Trust and Rosetrees Trust of the UK for their support. S.F. is grateful to the Center for Nanoscience and Nanotechnology of Tel Aviv University for the award of postdoctoral fellowship. ",
year = "2014",
month = jun,
day = "12",
doi = "10.1016/j.celrep.2014.04.024",
language = "אנגלית",
volume = "7",
pages = "1560--1576",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}