Age-dependent high-density clustering of GM1 ganglioside at presynaptic neuritic terminals promotes amyloid beta-protein fibrillogenesis.
The deposition of amyloid beta-protein (Abeta) is an invariable feature of Alzheimer's disease (AD); however, the biological mechanism underlying Abeta 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 Abeta assembly, which was suppressed by an antibody specific to GM1-bound Abeta, an endogenous seed for AD amyloid. Together with evidence that Abeta 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 Abeta deposition in AD.
Yamamoto
Naoki
N
Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan.
Matsubara
Teruhiko
T
Sato
Toshinori
T
Yanagisawa
Katsuhiko
K
D000375:Aging / Q000502:physiology*; D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D005456:Fluorescent Dyes / Q000378:metabolism; D005677:G(M1) Ganglioside / Q000378:metabolism*; D051379:Mice; D008959:Models, Neurological; D016501:Neurites / Q000378:metabolism*; D016716:PC12 Cells; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D013574:Synaptosomes / Q000378:metabolism / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D005677:G(M1) Ganglioside