Synaptophysin is a β-Amyloid Target that Regulates Synaptic Plasticity and Seizure Susceptibility in an Alzheimer's Model

Alzheimeru0027s 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 neurotransmission. 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 studies, we now demonstrate a profound seizure susceptibility phenotype in SYP knockout mice that is recapitulated in an AD model. Our studies imply a subtle yet critical role for SYP in the synaptic vesicle cycle and the etiology of AD.