Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice

Alexandra Bernardo, Fiona E. Harrison, Meghan McCord, Jiali Zhao, Aleksandra Bruchey, Sean S. Davies, L. Jackson Roberts, Paul M. Mathews, Yasuji Matsuoka, Toshio Ariga, Robert K Yu, Rebecca Thompson, Michael P. McDonald

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Gangliosides have been shown to be necessary for β-amyloid (Aβ) binding and aggregation. GD3 synthase (GD3S) is responsible for biosynthesis of the b- and c-series gangliosides, including two of the four major brain gangliosides. We examined Aβ-ganglioside interactions in neural tissue from mice lacking the gene coding for GD3S (St8sia1), and in a double-transgenic (APP/PSEN1) mouse model of Alzheimer's disease cross-bred with GD3S-/- mice. In primary neurons and astrocytes lacking GD3S, Aβ-induced cell death and Aβ aggregation were inhibited. Like GD3S-/- and APP/PSEN1 double-transgenic mice, APP/PSEN1/GD3S-/- "triple-mutant" mice are indistinguishable from wild-type mice on casual examination. APP/PSEN1 double-transgenics exhibit robust impairments on a number of reference-memory tasks. In contrast, APP/PSEN1/GD3S-/- triple-mutant mice performed as well as wild-type control and GD3S-/- mice. Consistent with the behavioral improvements, both aggregated and unaggregated Aβ and associated neuropathology were almost completely eliminated in triple-mutant mice. These results suggest that GD3 synthase may be a novel therapeutic target to combat the cognitive deficits, amyloid plaque formation, and neurodegeneration that afflict Alzheimer's patients.

Original languageEnglish (US)
Pages (from-to)1777-1791
Number of pages15
JournalNeurobiology of Aging
Volume30
Issue number11
DOIs
StatePublished - Nov 2009

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Apoptosis
  • Behavior
  • GD1a
  • GD1b GT1b
  • GD3
  • GD3 synthase
  • GM1
  • Gangliosides
  • Lipid rafts
  • Memory
  • Neuroinflammation
  • Oxidative stress
  • Plaque

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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