Lipid microdomain modification sustains neuronal viability in models of Alzheimer’s disease

Abstract

Decreased neuronal insulin receptor (IR) signaling in Alzheimer’s disease is suggested to contribute to synaptic loss and neurodegeneration. This work shows that alteration of membrane microdomains increases IR levels and signaling, as well as neuronal viability in AD models in vitro and in vivo. Neuronal membrane microdomains are highly enriched in gangliosides. We found that inhibition of glucosylceramide synthase (GCS), the key enzyme of ganglioside biosynthesis, increases viability of cortical neurons in 5xFAD mice, as well as in cultured neurons exposed to oligomeric amyloid-β-derived diffusible ligands (ADDLs). We furthermore demonstrate a molecular mechanism explaining how gangliosides mediate ADDL-related toxic effects on IR of murine neurons. GCS inhibition increases the levels of functional dendritic IR on the neuronal surface by decreasing caveolin-1-mediated IR internalization. Consequently, IR signaling is increased in neurons exposed to ADDL stress. Thus, we propose that GCS inhibition constitutes a potential target for protecting neurons from ADDL-mediated neurotoxicity and insulin resistance in Alzheimer’s disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0354-z) contains supplementary material, which is available to authorized users.

Deletion of Specific Sphingolipids in Distinct Neurons Improves Spatial Memory in a Mouse Model of Alzheimer’s Disease

“…The present study addresses the question of whether inhibition of ganglioside biosynthesis can also improve the cognitive capacity and counteract spine loss in 5xFAD mice. Intriguingly and in line with our previous work ( Herzer et al, 2016 ), behavioral tests indicate that spatial memory is improved in 5xFAD mice which harbor inducible GCS deletion in subsets of adult forebrain neurons. Additionally, these mice are protected from Aβ-induced spine loss.…”

“…Dynamic lipid microdomains in neuronal membranes are highly enriched in glucosylceramide synthase (GCS; gene: Ugcg )-derived gangliosides, a sub-class of glycosphingolipids. These gangliosides can directly modulate the activity of transmembrane receptors ( Nordström et al, 2013 ; Herzer et al, 2015 , 2016 ) and other membrane processes such as endocytosis ( Ewers et al, 2010 ). Ganglioside biosynthesis is altered in AD brains ( Ariga et al, 2008 ).…”

“…Moreover, gangliosides are suggested to destabilize mature Aβ fibrils and resolubilize them to synaptotoxic protofibrils ( Martins et al, 2008 ) and act as seeds for Aβ fibril formation ( Yanagisawa et al, 1995 ). We have shown that pharmacological GCS inhibition and subsequent reduction of gangliosides increase the resistance of cultured neurons toward oligomeric Aβ stress and protect from Aβ-induced loss of neuronal insulin receptors (IRs) ( Herzer et al, 2016 ; Nordström and Herzer, 2017 ). Moreover, we have found less neurodegeneration in transgenic 5x familial AD (5xFAD) mice ( Oakley et al, 2006 ) with a tamoxifen-inducible GCS deletion in forebrain neurons ( Herzer et al, 2016 ).…”

“…We have shown that pharmacological GCS inhibition and subsequent reduction of gangliosides increase the resistance of cultured neurons toward oligomeric Aβ stress and protect from Aβ-induced loss of neuronal insulin receptors (IRs) ( Herzer et al, 2016 ; Nordström and Herzer, 2017 ). Moreover, we have found less neurodegeneration in transgenic 5x familial AD (5xFAD) mice ( Oakley et al, 2006 ) with a tamoxifen-inducible GCS deletion in forebrain neurons ( Herzer et al, 2016 ). Thus, we hypothesized that GCS might be a potential novel therapeutic target for the treatment of AD.…”

Renal globotriaosylceramide facilitates tubular albumin absorption and its inhibition protects against acute kidney injury

“…SLs are complex lipids consisting of a ceramide with a sphingoid base coupled to a fatty acid (FA) and a carbohydrate moiety; they are involved in many cellular events including regulating membrane-receptor protein signaling, cell adhesion, and differentiation. [1][2][3] The neutral GSL Gb3 is a prominent GSL in the kidneys of mice and human beings. 4,5 In other cells, except renal cells, Gb3 has been defined as a cluster of differentiation (CD77); in B cells of the germinal centers of lymph nodes, Gb3 is assumed to modulate differentiation.…”