Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-β Levels in Primary Neurons from an Alzheimer’s Disease Transgenic Model
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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.
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.
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.
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.
KEY WORDSalzheimer’s disease amyloid-β APP/PS1 autophagy dihydroceramide desaturase 1
Amyloid β peptide
Amyloid precursor protein
Dihydroceramide desaturase 1
Dihydroceramide desaturase 2
Familial alzheimer’s disease
Microtubule-associated protein 1A/1B–light chain 3
Polymerase chain reaction
Trans golgi network
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”.
- 19.Siddique MM, Li Y, Wang L, Ching J, Mal M, Ilkayeva O, et al. Ablation of dihydroceramide desaturase 1, a therapeutic target for the treatment of metabolic diseases, simultaneously stimulates anabolic and catabolic signaling. Mol Cell Biol. 2013;33(11):2353–69.CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Caccamo A, De Pinto V, Messina A, Branca C, Oddo S. Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer's disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature. J Neurosci: Off J Soc Neurosci. 2014;34(23):7988–98.CrossRefGoogle Scholar