RT Journal Article
SR Electronic
T1 Synaptophysin is a β-Amyloid Target that Regulates Synaptic Plasticity and Seizure Susceptibility in an Alzhiemer’s Model
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 129551
DO 10.1101/129551
A1 Daniel J. Adams
A1 Chong Shen
A1 Josien Levenga
A1 Tamara Basta
A1 Stephen P. Eisenberg
A1 James Mapes
A1 Lukas Hampton
A1 Kelly Grounds
A1 Charles A. Hoeffer
A1 Michael H. B. Stowell
YR 2017
UL http://biorxiv.org/content/early/2017/04/25/129551.abstract
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.