APP Homodimers Transduce an Amyloid-β-Mediated Increase in Release Probability at Excitatory Synapses

被引：96

作者：

Fogel, Hilla ^{[1
]}

Frere, Samuel ^{[1
]}

Segev, Oshik ^{[1
]}

Bharill, Shashank ^{[4
,5
]}

Shapira, Ilana ^{[1
]}

Gazit, Neta ^{[1
,2
]}

O'Malley, Tiernan ^{[6
,7
]}

Slomowitz, Edden ^{[1
]}

Berdichevsky, Yevgeny ^{[1
]}

Walsh, Dominic M. ^{[7
]}

Isacoff, Ehud Y. ^{[4
,5
]}

Hirsch, Joel A. ^{[3
]}

Slutsky, Inna ^{[1
,2
]}

机构：

[1] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel

[2] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel

[3] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Biochem & Mol Biol, IL-69978 Tel Aviv, Israel

[4] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[5] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA

[6] Univ Coll Dublin, Conway Inst, Sch Biomol & Biomed Sci, Lab Neurodegenerat Res, Dublin 4, Ireland

[7] Harvard Inst Med, Brigham & Womens Hosp, Ctr Neurol Dis, Lab Neurodegenerat Res, Boston, MA 02115 USA

来源：

CELL REPORTS | 2014年 / 7卷 / 05期

基金：

欧洲研究理事会; 以色列科学基金会;

关键词：

PRECURSOR PROTEIN; ALZHEIMERS-DISEASE; HIPPOCAMPAL HYPERACTIVITY; SYNAPTIC PLASTICITY; SECRETED OLIGOMERS; MOUSE MODEL; IN-VIVO; DOMAIN; LOCALIZATION; GENERATION;

D O I：

10.1016/j.celrep.2014.04.024

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Accumulation of amyloid-beta peptides (A beta), 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 A beta 40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. A beta 40 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/G(i/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 A beta 40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer's disease.

引用

页码：1560 / 1576

页数：17