Editors' ChoiceStem Cells

The importance of lipid for the Alzheimer's brain

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Science Translational Medicine  23 Sep 2015:
Vol. 7, Issue 306, pp. 306ec161
DOI: 10.1126/scitranslmed.aad3618

Brain lipid metabolism is altered in Alzheimer's disease and, Hamilton and colleagues report, also affects the production and maintenance of stem cells in the forebrain. In Alzheimer's patients and in a transgenic mouse model of the disease, these authors found large droplets of oleic acid (OA) within brain ependymal cells, ciliated barrier cells lining the cerebral ventricles that propel the cerebral spinal fluid. Buildup of neutral lipids was associated with the quiescence of neural stem cells in the subventricular zone. Blockade of oleic acid synthesis reactivated the stem cells.

Oleic acid (OA)—highly enriched in olive oil—is produced in the body from stearic acid by stearoyl-CoA desaturase, an enzyme known to be overactive in the frontal and temporal cortex of Alzheimer's patients. Although OA can act as a neuronal growth– promoting factor in the subventricular zone, Hamilton et al. now report that at higher doses, it inhibits in vitro neurosphere formation and in vivo stem cell proliferation.

To test the origin of the ependymal lipid inclusions, Hamilton et al. injected 13C labeled oleic acid into the ventricles of normal mice over a week and found that triglyceride deposits similar to the ones in Alzheimer's patients built up in the same region of the subventricular zone. Microarray analysis of the subventricular zone in Alzheimer's and control mice showed differential expression of lipid regulatory genes, indicating perturbation of lipid metabolism in this stem cell niche.

Oleic acid–caused neural progenitor cell failure may be related to the global cognitive failure of Alzheimer's, but also it may be a byproduct of a disturbed metabolic milieu or a dysregulated attempt to promote growth. The most interesting translational feature of this paper is that the authors link a localized lipid dysregulation with Alzheimer's pathology in humans, as well as an animal model of the disease, and show that ependymal cells are involved at very early disease stages. Future work will need to look at system-level approaches to metabolic disruption in Alzheimer's.

L. K. Hamilton et al., Aberrant lipid metabolism in the forebrain niche suppresses adult neural stem cell proliferation in an animal model of Alzheimer's disease. Cell Stem Cell 10.1016/j.stem.2015.08.001 (2015). [Abstract]

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