Alzheimer’s disease risk gene undermines insulation of brain ‘wiring’ — ScienceDaily

A new study combines evidence from postmortem human brains, lab-based human brain cell cultures, and Alzheimer’s disease model mice to show that one or more copies of APOE4, rather than the more common and risk-neutral APOE3 version, If there are two, cells called oligodendrocytes mismanage cholesterol, transport fat molecules, and wrap the long vine-like axonal “wires” that neurons project to create brain circuit connections. can not. Deficiency of this fatty insulator, called myelin, can be a significant contributor to the pathology and symptoms of Alzheimer’s disease. This is because without proper myelination, communication between neurons is compromised.

A recent study by a research group led by Professor Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and Aging Brain Initiative, has discovered distinct ways in which APOE4 disrupts the way fat molecules or lipids are processed. did. Major brain cell types such as neurons, astrocytes, and microglia. Whether it’s new research or those studies, the team has identified compounds appearing in the lab to correct these various problems, generating potential drug-based treatment strategies.

A new study will not only discover how APOE4 disrupts myelination, but also to compare how gene expression differs in people with APOE4 compared to APOE3, using a single nucleus. We extend that work by providing the first systematic analysis across major brain cell types using RNA sequencing (snRNAseq).

“This paper very clearly shows, from snRNAseq of post-mortem human brains, that APOE4 very clearly affects different brain cell types in a genotype-specific manner,” said MIT. says Tsai, a member of the Department of Brain and Cognitive Sciences at . , they are all different.

“We feel that lipid dysregulation may be this very fundamental biology that underlies many of the pathologies we observe.

The first authors of the paper are Joel Blanchard, assistant professor at the Icahn School of Medicine, Mount Sinai, who began his work as a postdoc in Tsai’s MIT lab; Djuna Von Maydell and Leyla Akay, graduate students in Tsai’s lab; My name is Jose Davila Velderrain. , Human Technopole research group leader and co-corresponding author. He is a professor of computer science at MIT.

Many ways to examine myelination

Post-mortem human brain samples were obtained from the Congregational Research and Rush’s Memory and Aging Project. The team’s snRNAseq results are a dataset that von Maydell has made freely available, encompassing more than 160,000 individual cells of 11 different types from the prefrontal cortex of 32 individuals, including two him. eight, including an APOE4 copy of . APOE3/3 and his APOE3/4 samples were balanced by Alzheimer’s disease diagnosis, gender and age. All her APOE4/4 carriers had Alzheimer’s disease and 5 of 8 were female.

Some results mirrored known Alzheimer’s disease pathology, while others were novel. One in particular showed that APOE4-carrying oligodendrocytes exhibited greater expression of cholesterol synthesis genes and disrupted cholesterol transport. The more copies of APOE4, the greater the effect. This was of particular interest given the results of a previous analysis by the Tsai and Kellis lab in 2019 linking Alzheimer’s disease with decreased expression of oligodendrocyte myelination genes.

Direct tissue observation using a variety of techniques has shown that APOE4 brains have an abnormal amount of cholesterol accumulation, particularly in the cell bodies of oligodendrocytes, but relatively depleted around nerve axons. It turns out that there is

To understand why, the team used patient-derived induced pluripotent stem cells to create laboratory cell cultures of oligodendrocytes engineered to differ only in whether they have APOE4 or APOE3. Did. Again he showed that APOE4 cells showed major lipid disruption. In particular, diseased oligodendrocytes store excess cholesterol in the body, and the excess internal fat shows signs of stressing the organelles called the endoplasmic reticulum, which are involved in cholesterol transport, and actually release cholesterol into membranes. Subsequently, when co-cultured with neurons, APOE4 oligodendrocytes, like APO3 cells, failed to myelinate neurons, regardless of whether the neurons harbored APOE4 or APOE3.

The team also observed less myelination in the postmortem brain in APOE4 carriers than in APOE3 carriers. , was significantly thinner in APOE4 brains. Humans did the same with mice engineered to have APOE4 and mice engineered to have APOE3.

productive intervention

Eager to find potential interventions, the team focused on drugs that affect cholesterol, such as statins (which inhibit synthesis) and cyclodextrins, which help transport cholesterol. However, application of cyclodextrin to dish-cultured APOE4 oligodendrocytes reduced intracellular cholesterol accumulation and improved myelination in co-culture with neurons. had the effect of

Finally, the team administered cyclodextrin to some APOE4 mice, left others untreated, and administered two different memory tests to all mice. Cyclodextrin-treated mice performed significantly better on both tests, suggesting a link between improved myelination and improved cognition.

Tsai said a clear picture is emerging that interventions to correct specific lipid dysregulation by cell type could help counteract APOE4’s contribution to Alzheimer’s disease. rice field.

“It’s encouraging to see a way to rescue oligodendrocyte function and myelination in lab and mouse models,” said Tsai. “However, in addition to oligodendrocytes, we may need to find clinically effective ways to treat microglia, astrocytes, and the vasculature to actually combat disease.”

Other authors on this paper include Hansruedi Mathys, Shawn Davidson, Audrey EffenbergerChi0yu Chen, Kristan Maner-Smith, Ihab Jahhar, Eric Orlund, Michael Bula, Emre Agbas, Ayesha Ng., Xueqiao Jiang, Martin Kahn, Cristina Blanco-Duque , Nicholas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Talin, Tak Ko, William Ralvenius, David Bennett, Hugh Cam.

The Robert A. and Renee E. Belfer Foundation, JPB Foundation, Carol and Gene Ludwig Family Foundation, Cure Alzheimer’s Fund, and the National Institutes of Health funded this research.