This cholesterol is good for the brain

While cholesterol is bad for the heart, the brain needs it in copious amounts. Nearly 25% of the cholesterol in the body is found in the brain. Cholesterol not only protects brain cells but facilitates quick transmission of electrical impulses in the axons, the primary transmission lines of the nerve cells. Hence it is key to ensuring healthy cognitive function.

Using a mouse model, an Indo-French research team found that cholesterol biosynthesis is compromised in Alzheimer's disease (AD), leading to lower cognitive abilities. The team corroborated this further by examining post-mortem samples of 11 human AD patients. It found that a small biomolecule synthesised in the lab can actually restore cholesterol production to healthy levels in AD-affected mice. The study was published in Neurobiology of Disease (bit.ly/AD-brain).

The scientists found that acetylation of histones – basic proteins found in amino acids like lysine – is very low in genes associated with cholesterol biosynthesis in mouse brains. Poor histone acetylation would mean lower production of cholesterol in the brain. Another trouble with low histone acetylation is that it leaves behind relatively higher levels of a crucial metabolite called acetyl-CoA, which is otherwise essential for biochemical reactions involving histones. "When this acetyl-CoA is available in ample quantities, it will go and induce acetylation somewhere else and this, in turn, would disturb the cognitive functions in the brain," says Tapas Kumar Kundu, Professor, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, who played a key role in discovering the small molecule activator of acetylation in the brain known as CSP-TTK21. "The cholesterol biosynthesis pathway in the brain came back to normal levels with the administration of the CSP-TTK21 molecule."

This discovery is the result of a long collaboration between Kundu and Anne-Laurence Boutillier of the University of Strasbourg, France. It calls into question the use of statins (popularly prescribed to lower blood cholesterol) in AD patients. It cautions that there is a strong possibility of fat-dissolving statin molecules crossing the blood-brain barrier, affecting the cholesterol availability in the brain of AD patients who already have a compromised cholesterol-making machinery.

"What is important is that this molecule has shown the potential to restore cognitive function…(at) late-stage AD," says Sourav Banerjee of the National Brain Research Centre, who was not involved in the research. "Nobody in the past has shown that restoring cholesterol production can have beneficial effects on the brains in which much of the hippocampal neurons, which are important for memory retention, degenerated and the plaque has spread."