Modulation of Brain Cholesterol: a New Line of Research in Alzheimer’s Disease Treatment?

18 Sep 2015 --- We have known for some years that Alzheimer’s disease is characterized by two types of lesions, amyloid plaques and degenerated tau protein. Cholesterol plays an important role in the physiopathology of this disease. Two French research teams (Inserm/CEA/University of Lille/University of Paris-Sud) have just shown, in a rodent model, that over expressing an enzyme that can eliminate excess cholesterol from the brain may have a beneficial action on the tau component of the disease, and completely correct it. This is the first time that a direct relationship has been shown between the tau component of Alzheimer’s disease and cholesterol. This work is published in the September 2015 issue of Human Molecular Genetics.

Excess brain cholesterol cannot freely cross the blood-brain barrier; to be eliminated it must be converted into 24-hydroxycholesterol (24-OHC) by the liver enzyme CYP46A1. At Inserm, Nathalie, Cartier, coordinator of this work, and Patrick Aubourg, director of the unit, proposed the hypothesis that increasing the efflux of cholesterol from the brain by over expressing CYP46A1 might have a beneficial effect on the elements of Alzheimer pathology.

They showed that injecting CYP46A1 effectively corrects a mouse model of amyloid pathology of the disease. CYP46A1 thus appears to be a therapeutic target for Alzheimer’s disease.

Conversely, in vivo inhibition of CYP46A1 in the mice induced an increase in the production of Aß peptides, abnormal tau protein, neuronal death and hippocampal atrophy, leading to memory problems. Together, these elements reproduce a phenotype mimicking Alzheimer’s disease. These results demonstrate the key role of cholesterol in the disease, and confirm the relevance of CYP46A1 as a potential therapeutic target. Taken together, this work now enables the research team to propose a gene therapy approach for Alzheimer’s disease in people for whom there is no available treatment.

This research also raises questions as to how brain cholesterol becomes elevated in the first place as a possible prevention approach may be useful. Contrary to popular belief, cholesterol levels vary minimally in response to dietary intake of this steroid hormone. Cholesterol in fact, is such a crucial part of the body that if dietary intake falls too low, the liver will produce more of it to keep levels healthy. Cholesterol in the body is not fabricated from cholesterol from dietary sources, but from sugars, which form the building blocks of it. In order to achieve healthy cholesterol levels therefore, it is important to keep dietary sugars and starchy carbohydrates to a minimum.