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

Alzheimers Dement. 2023 May;19(5):2095-2116. doi: 10.1002/alz.12835. Epub 2022 Nov 12.


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.

Keywords: APP; Alzheimer's disease; Down syndrome; Dp16; SNARE complex; aging; partial trisomy 21; synaptic protein.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Down Syndrome* / metabolism
  • Mice
  • SNARE Proteins


  • Amyloid beta-Protein Precursor
  • Amyloid beta-Peptides
  • SNARE Proteins