Modification of membrane lipids protects neurons against insulin resistance in models of Alzheimer's disease

Abstract

Alzheimer's disease is a degenerative disease of the central nervous system, which leads to severe deficits in memory and orientation by a progressive loss of neurons and synapses. Soluble β-amyloid oligomers are highly neurotoxic precursors of β-amyloid fibrils that accumulate in Alzheimer's disease. Binding of β-amyloid oligomers to synaptic insulin receptors leads to neuronal insulin resistance, which significantly contributes to cognitive impairments. Insulin receptors are located in the cell membrane, which consists of a lipid bilayer and contains high amounts of glycosylated lipids, the so-called gangliosides. Ganglio-sides regulate insulin receptor activity via dynamic molecular interactions and facilitate the β-amyloid oligomer-induced insulin resistance. Thus, inhibiting ganglioside biosynthesis can protect neurons from the detrimental effects of β-amyloid oligomers.