Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-β Levels in Primary Neurons from an Alzheimer’s Disease Transgenic Model

ABSTRACT

Purpose

The induction of autophagy has recently been explored as a promising therapeutic strategy to combat Alzheimer’s disease. Among many other factors, there is evidence that ceramides/dihydroceramides act as mediators of autophagy, although the exact mechanisms underlying such effects are poorly understood. Here, we describe how two dihydroceramide desaturase inhibitors (XM461 and XM462) trigger autophagy and reduce amyloid secretion by neurons.

Methods

Neurons isolated from wild-type and APP/PS1 transgenic mice were exposed to the two dihydroceramide desaturase inhibitors to assess their effect on these cell’s protein and lipid profiles.

Results

Both dihydroceramide desaturase inhibitors increased the autophagic vesicles in wild-type neurons, reflected as an increase in LC3-II, and this was correlated with the accumulation of dihydroceramides and dihydrosphingomyelins. Exposing APP/PS1 transgenic neurons to these inhibitors also produced a 50% reduction in amyloid secretion and/or production. The lipidomic defects triggered by these dihydroceramide desaturase inhibitors were correlated with a loss of S6K activity, witnessed by the changes in S6 phosphorylation, which strongly suggested a reduction of mTORC1 activity.

Conclusions

The data obtained strongly suggest that dihydroceramide desaturase 1 activity may modulate autophagy and mTORC1 activity in neurons, inhibiting amyloid secretion and S6K activity. As such, it is tantalizing to propose that dihydroceramide desaturase 1 may be an important therapeutic target to combat amyloidosis.

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Abbreviations

Aβ:

Amyloid β peptide

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

BafA1:

Bafilomycin A

Cer:

Ceramides

Des1:

Dihydroceramide desaturase 1

Des2:

Dihydroceramide desaturase 2

dhCer:

Dihydroceramides

FAD:

Familial alzheimer’s disease

LC3:

Microtubule-associated protein 1A/1B–light chain 3

MTT:

[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]

p62:

Nucleoporin p62

PCR:

Polymerase chain reaction

PS1:

Presenilin 1

RV:

Resveratrol

SLs:

Sphingolipids

TGN:

Trans golgi network

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported by a grant from the Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED; an initiative of the ISCIII). In addition, work in FW’s lab was supported by grants from the “Plan Nacional”, “Dirección General de Ciencia y Tecnología - DGCYT SAF2012-39148-C03-01; and Proyectos I+D+i Retos 2015 SAF2015-70368-R, and an Institutional grant from the” Fundación Areces”.

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Correspondence to Lara Ordóñez-Gutiérrez.

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Guest Editor: Davide Brambilla

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Ordóñez-Gutiérrez, L., Benito-Cuesta, I., Abad, J.L. et al. Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-β Levels in Primary Neurons from an Alzheimer’s Disease Transgenic Model. Pharm Res 35, 49 (2018). https://doi.org/10.1007/s11095-017-2312-2

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KEY WORDS

  • alzheimer’s disease
  • amyloid-β
  • APP/PS1
  • autophagy
  • dihydroceramide desaturase 1