PT  - JOURNAL ARTICLE
AU  - Daniel J. Adams
AU  - Chong Shen
AU  - Josien Levenga
AU  - Tamara Basta
AU  - Stephen P. Eisenberg
AU  - James Mapes
AU  - Lukas Hampton
AU  - Kelly Grounds
AU  - Charles A. Hoeffer
AU  - Michael H. B. Stowell
TI  - Synaptophysin is a β-Amyloid Target that Regulates Synaptic Plasticity and Seizure Susceptibility in an Alzhiemer’s Model
AID  - 10.1101/129551
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 129551
4099  - http://biorxiv.org/content/early/2017/04/25/129551.short
4100  - http://biorxiv.org/content/early/2017/04/25/129551.full
AB  - Alzheimer’s disease (AD), a condition characterized by cognitive deficits and progressive loss of memory, is causally linked to the short amyloid peptide Aβ42, which disrupts normal neurotransmission1,2. Neurotransmitter (NT) release from synaptic vesicles (SV) requires coordinated binding of the conserved core secretory machinery comprised of the soluble NSF attachment protein receptor (vSNARE) synaptobrevin 2 (VAMP2) on the SV and the cognate tSNAREs on the plasma membrane. Synaptophysin (SYP) is the most abundant SV protein3 and the major pre-fusion binding partner of VAMP24. A major challenge in understanding the etiology and prevention of AD is determining the proteins directly targeted by Aβ42 and elucidating if these targets mediate disease phenotypes. Here we demonstrate that Aβ42 binds to SYP with picomolar affinity and disrupts the SYP/VAMP2 complex resulting in inhibition of both neurotransmitter release and synaptic plasticity. While functionally redundant paralogs of SYP have masked its critical activity in knockout studies5,6, we now demonstrate a profound seizure susceptibility phenotype in SYP knockout mice that is recapitulated in an AD model mouse. Our studies imply a subtle yet critical role for SYP in the synaptic vesicle cycle and the etiology of AD.