cortex

Project number:

802

Project title:

Cholesterol role in neurodegenerative and demyelinating diseases

Project supervisor:

Hasan Mohajeri, Division of Psychiatry Research, University of Zurich

Project description:

Sophisticated regulatory systems have evolved for the maintenance of cholesterol homeostasis in the CNS. All cholesterol of the CNS is originated from de novo synthesis, because the blood-brain barrier prevents cholesterol uptake from the circulation. CNS cholesterol resides in two pools. One represented by the myelin sheaths (ie, oligodendroglia) and the other by the plasma membranes of astrocytes and neurons. 70% of brain cholesterol is associated with myelin. It has been estimated that during myelination of the human brain an active oligodendrocyte may synthesize 3-times its own weight as myelin each day. Moreover, cholesterol is a precursor of several hormones, involved in signaling pathways and modulates several enzyme activities in the brain. Changes in the integrity of myelin have been demonstrated in normal aging and Alzheimer’s disease and demyelization occurs increasingly in connection with active periods of multiple sclerosis.

DHCR24 is the enzyme responsible for synthesis of cholesterol from its precursor desmosterol. Depletion of Dhcr24 gene leads to the elimination of cholesterol and accumulation of desmosterol in brain tissue.

The aim of this project is to investigate the role of cholesterol in myelination in health and disease. We will investigate the effects of cholesterol deficiency on myelin integrity and structure in DHCR24+/- and DHCR24-/- CNS. We will study whether desmosterol can partially substitute cholesterol and whether this process depends on aging. We will employ mice expressing the green fluorescent protein (GFP) under the beta-actin promoter to isolate sub-ventricular zone stem cells. These cells will be administered to the mice by intravenous injection. GFP positive cells will be easily detectable in the blood and CNS of implanted mice. We and others have shown that these cells have morphological and immunocytochemical characteristics of oligodendrocytes in vitro and in vivo. It is important to establish whether these cells are capable of functional differentiation into oligodendrocytes to generate normal myelin following intravenous administration. A model of demyelination such as EAE or PLP transgenic mouse will be used as a control. The proposed project could significantly advance the field of brain cytotherapy by establishing a non-invasive model for engraftment in a model applicable to neurodegenerative and demyelinating diseases.

Possible cortex partners for rotation:

In cooperation with the Berlin partner (U. Dirnagl): investigations of the integrity of the blood-brain barrier and the extent of inflammation in brains of DHCR24 homozygous, heterozygous mice and their wildtype controls by confocal laser scanning microscopy. How do aging or remyelination by grafted cells change the integrity of the blood-brain barrier or the inflammation?

In collaboration with the London partner (F. Edwards): measurement of the LTP of untreated versus treated mice.

In cooperation with the Prague partner (E. Sykova): investigations of distribution and fate of implanted cells by nuclear magnetic resonance imaging (MRI). Also, electrophysiological properties of the implanted cells can be determined.