Reduced synaptic proteins and SNARE complexes in Down syndrome with Alzheimer's disease and the Dp16 mouse Down syndrome model: Impact of APP gene dose

Introduction: Synaptic failure, a hallmark of Alzheimer's disease (AD), is correlated with reduced levels of synaptic proteins. Though people with Down syndrome (DS) are at markedly increased risk for AD (AD-DS), few studies have addressed synapse dysfunction.

Methods: Synaptic proteins were measured in the frontal cortex of DS, AD-DS, sporadic AD cases, and controls. The same proteins were examined in the Dp16 model of DS.

Results: A common subset of synaptic proteins were reduced in AD and AD-DS, but not in DS or a case of partial trisomy 21 lacking triplication of APP gene. Pointing to compromised synaptic function, the reductions in AD and AD-DS were correlated with reduced SNARE complexes. In Dp16 mice reductions in syntaxin 1A, SNAP25 and the SNARE complex recapitulated findings in AD-DS; reductions were impacted by both age and increased App gene dose.

Discussion: Synaptic phenotypes shared between AD-DS and AD point to shared pathogenetic mechanisms.