Age-dependent high-density clustering of GM1 ganglioside at presynaptic neuritic terminals promotes amyloid β-protein fibrillogenesis

Abstract

The deposition of amyloid β-protein (Aβ) is an invariable feature of Alzheimer's disease (AD); however, the biological mechanism underlying Aβ assembly into fibrils in the brain remains unclear. Here, we show that a high-density cluster of GM1 ganglioside (GM1), which was detected by the specific binding of a novel peptide (p3), appeared selectively on synaptosomes prepared from aged mouse brains. Notably, the synaptosomes bearing the high-density GM1 cluster showed extraordinary potency to induce Aβ assembly, which was suppressed by an antibody specific to GM1-bound Aβ, an endogenous seed for AD amyloid. Together with evidence that Aβ deposition starts at presynaptic terminals in the AD brain and that GM1 levels significantly increase in amyloid-positive synaptosomes prepared from the AD brain, our results suggest that the age-dependent high-density GM1 clustering at presynaptic neuritic terminals is a critical step for Aβ deposition in AD.