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.
Highlights
Alzheimer’s disease is characterized by progressive neurodegeneration and loss of cognitive abilities
Inhibition of glucosylceramide synthase (GCS)-mediated ganglioside biosynthesis by GENZ increases resistance towards amyloid-β-derived diffusible ligands (ADDLs) and insulin receptor (IR) signaling in mHippoE-14 neurons Major neuronal gangliosides GM1, GD1a, GD1b, and GT1b are generated by the sequential addition of carbohydrate moieties to glucosylceramide (Fig. 1a)
We found that treatment with 5 μM GENZ for 7 days efficiently inhibited GCS activity and subsequent ganglioside biosynthesis (Fig. 1b)
Summary
Alzheimer’s disease is characterized by progressive neurodegeneration and loss of cognitive abilities. Even though senile plaques containing Aβ fibrils accumulate in the brain as the disease progresses, soluble oligomeric Aβ species have been hypothesized to be the major neurotoxic agents in Alzheimer’s disease [31]. Accumulating evidence suggests that dysregulation of brain insulin receptor (IR) signaling is associated with the pathogenesis of Alzheimer’s disease [11, 15, 28, 57]. Oligomeric amyloid-β-derived diffusible ligands (ADDLs) [22, 47] are spherical Aβ aggregates, with sizes ranging from 3 to 5 nm [31]. Increasing IR signaling has emerged as a potential therapeutic target in Alzheimer’s disease [41]
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