Alzheimer's gene variant disrupts lipids and cholesterol in the brain

A gene variant which increases risk of developing Alzheimer's disease may do so by decreasing production of the substance which insulates nerve cells.

Different variants of the APOE gene are associated with different risks of developing the neurodegenerative condition Alzheimer's disease. The APOE4 variant significantly increases the risk of developing Alzheimer's, compared to the most common variant, APOE3. A new study published in Nature, suggests a mechanism for this effect.

'Mounting evidence shows that APOE4 disrupts how different brain cells process lipids including cholesterol and that this underlying biology may contribute significantly to the pathology of Alzheimer's disease,' said lead author Professor Li-Huei Tsai from the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts.

Myelin is a fatty substance that insulates nerve cells to speed up their signalling and provide them with metabolic support. To produce the myelin, brain cells called oligodendrocytes need to uptake, synthesize, and transport lipids like cholesterol, a process which requires the APOE protein encoded by the APOE gene.

To investigate the link between APOE4, lipid regulation and myelin, researchers at MIT and Mount Sinai Hospital in New York used a method known as single-cell transcriptomics to investigate gene expression in post-mortem brain samples from people with Alzheimer's, comparing APOE4 carriers with non-carriers.

They found that APOE4 carriers had significantly altered expression of genes involved in cholesterol synthesis and transport – especially in oligodendrocytes – and downregulation of genes linked to myelination. Furthermore, using techniques to look directly at the brain tissue, researchers saw that APOE4-carriers had abnormal accumulation of cholesterol within oligodendrocytes, and not surrounding nerve cells where it should be.

They then created human oligodendrocytes in a dish from induced pluripotent stem cells (iPSCs), engineered to carry either APOE4 or APOE3. APOE4-carrying oligodendrocytes had more accumulated cholesterol and decreased production of myelin components. Similar evidence of cholesterol and myelin dysregulation was also seen in a mouse model carrying the APOE4 variant.

Lastly, the researchers used the drug cyclodextrin, which facilitates cholesterol transport, to try to reduce cholesterol accumulation so it instead gets incorporated into myelin. In both the in vitro cells and mouse model, cyclodextrin decreased the accumulation of cholesterol, increased production of myelin components and increased myelination.

Biochemist Professor Irina Pikuleva, from Case Western Reserve University in Cleveland, Ohio who was not involved in the study, said: 'This study highlights the importance of cholesterol in the brain… and we now need to try all available strategies to target brain cholesterol.'