MIT researchers study genes that are 'significant contributor' to Alzheimer's

The Massachusetts Institute of Technology announced that a team of researchers published a study that showed key information pertaining to Alzheimer’s disease.

The study was published in Nature on November 16, and shows that the APOE4 gene variant has consequences for the brain on a cell-by-cell basis, according to a November 22 report by MIT News. The study found that when people have one or two copies of APOE4 rather than the common and risk-neutral APOE3 version, cells called oligodendrocytes do not transport cholesterol to the myelin. Myelin is fatty insulation wrapping the axon wiring that neurons project to connect brain circuits.

“Deficiency of this fatty insulation, called myelin, may be a significant contributor to the pathology and symptoms of Alzheimer’s disease because without proper myelination, communications among neurons are degraded,” the report stated.

Researchers used postmortem human brains, as well as lab-based human brain cell cultures and model mice to display how APOE4 is disrupting myelination and to provide the first systematic analysis across brain cell types using single nucleus RNA sequencing (snRNAseq). This is to compare how gene expression is different with people who have APOE3 compered to APOE4.

The results involved more than 160,000 cells of 11 different types from the prefrontal cortex of 32 people. This includes 12 with two APOE3 copies, 12 with a copy of each APOE3 and APOE4, and eight with two APOE4 copies.

The research group, led by MIT Professor Li-Huei Tsai, director of The Picower Institute for Learning and Memory and the Aging Brain Initiative at MIT, has found compounds that show they are correcting the problems associated with APOE4. This could lead to potential pharmaceutical-based treatment.

“It’s encouraging that we’ve seen a way to rescue oligodendrocyte function and myelination in lab and mouse models,” MIT Professor Li-Huei Tsai said in the report. “But in addition to oligodendrocytes, we may also need to find clinically effective ways to take care of microglia, astrocytes, and vasculature to really combat the disease.”

The authors of the paper include: Joel Blanchard, assistant professor at Mt. Sinai’s Icahn School of Medicine who began the work as a postdoc in Tsai’s lab; Djuna Von Maydell and Leyla Akay, who are both graduate students working in Tsai’s lab; and Jose Davila Velderrain, a research group leader at Human Technopole and former postdoc in the lab of co-corresponding author and computer science professor Manolis Kellis.