Prevention of amyloid ß fibril deposition on the synaptic membrane in the precuneus by ganglioside nanocluster-targeting inhibitors.

ABSTRACT

Alzheimer's disease (AD), a progressive neurodegenerative condition, is one of the most common causes of dementia. Senile plaques, a hallmark of AD, are formed by the accumulation of amyloid ß protein (Aß), which starts to aggregate before the onset of the disease. Gangliosides, sialic acid-containing glycosphingolipids, play a key role in the formation of toxic Aß aggregates. In membrane rafts, ganglioside-bound complexes (GAß) act as nuclei for Aß assembly, suggesting that GAß is a promising target for AD therapy. The formation of GAß-induced Aß assemblies has been evaluated using reconstituted planar lipid membranes composed of synaptosomal plasma membrane (SPM) lipids extracted from human and mouse brains. Although the effects of gangliosides on Aß accumulation in the precuneus have been established, effects on Aß fibrils have not been determined. In this study, Aß42 fibrils on reconstituted membranes composed of SPM lipids prepared from the precuneus cortex of human autopsied brains were evaluated by atomic force microscopy. In particular, Aß42 accumulation, as well as the fibril number and size were higher for membranes with precuneus lipids than for membranes with calcarine cortex lipids. In addition, artificial peptide inhibitors targeting Aß-sensitive ganglioside nanoclusters cleared Aß assemblies on synaptic membranes in the brain, providing a novel therapeutic strategy for AD.