Alzheimer's risk gene may change fat processing in brain cells

A genetic variant linked to Alzheimer's disease impairs the production of the fatty layer that insulates neurons by disrupting an important signalling pathway.

A variant known as APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease. Previous research led by Professor Li-Huei Tsai at the Massachusetts Institute of Technology showed that APOE4 was associated with brain cells called oligodendrocytes struggling to correctly produce myelin, the fat-based insulation that allows neurons to work properly (see BioNews 1168). The team now report having used a CRISPR-based screening approach to better understand the biological mechanisms involved, revealing impairments in the key cell signalling pathway Wnt.

'I think this type of screen not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development,' said Professor Tsai, the senior author of the study published in Cell Stem Cell.

The protein encoded by the APOE gene helps package and transport cholesterol, an important step in the production of myelin by oligodendrocytes. In individuals carrying APOE4, these cells had been found to abnormally accumulate cholesterol, and their myelin production was disrupted.

To investigate why this is the case, the team relied on induced pluripotent stem cells (iPSCs) to create APOE4-carrying human oligodendrocytes in a dish. They then performed a genome-wide screen, using CRISPR to knock out every protein-coding gene in the human genome one at a time.

The experiments revealed that the oligodendrocytes had decreased Wnt pathway signalling, a molecular cascade particularly important in development. In addition, the team found increased activity of an enzyme called glycogen synthase kinase-3 beta (GSK3B), which suppresses the Wnt pathway. Further work which also relied on cells from human brain tissue collected after death confirmed that, in APOE4 carriers, genes promoting Wnt signaling were less accessible for transcription.

Next, the researchers examined the impact of a drug that suppresses the GSK3B enzyme and aims to restore the activity of the Wnt signalling pathway. Inhibiting GSK3B led to reduced lipid accumulation and greater production of insulating myelin in the iPSC-derived oligodendrocytes grown alongside neurons. The drug had a similar effect when given to mice who were genetically modified to carry the APOE4 variant.

More work is required to confirm these early-stage findings, and to better understand the molecular processes connecting myelin production and impairments in the Wnt pathway. In addition, the team has expressed interest in further investigating the role of GSK3B, which has already been linked to another major hallmark of Alzheimer's disease, known as tau phosphorylation.