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

It’s common knowledge that carrying one copy of the APOE4 gene variant increases the risk of Alzheimer’s threefold, and carrying two about tenfold, but the underlying causes and what can be done to help patients remain largely unknown. Research published by a team at the Massachusetts Institute of Technology on November 16 in Nature provides some new answers as part of a broader line of research that has demonstrated the effects of APOE4 on cell types in the brain.

The new study combines data from postmortem human brains, laboratory cultures of human brain cells, and mouse models of Alzheimer’s disease to show that when people have one or two copies of APOE4, rather than the more common and risk-neutral version of APOE3, cells, called oligodendrocytes mismanagement of cholesterol, unable to transport a molecule of fat to wrap around the long wine-like axon “wiring” that neurons project to make connections brain circuits. Deficiency in this fatty insulation, called myelin, may contribute significantly to the pathology and symptoms of Alzheimer’s disease because without proper myelination, communication between neurons deteriorates.

Recent research by a research team led by Picower Professor Li-Hui Tsai, director of the Picower Learning and Memory Institute and MIT’s Brain Aging Initiative, found that APOE4 disrupts the functioning of fat or lipid molecules. key cell types in the brain including neurons, astrocytes and microglia. In the new study, as well as those, the team identified compounds that appear in the lab to correct these various problems, providing potential pharmaceutical-based treatment strategies.

The new study extends this work not only by revealing how APOE4 disrupts myelination, but also by conducting the first systematic analysis of major brain cell types using single-stranded RNA sequencing (snRNAseq) to compare how different gene expression is in people with APOE4 and APOE3 .

“This paper shows very clearly from postmortem human brain snRNAseq in a genotype-specific manner that APOE4 very clearly affects different brain cell types,” said Tsai, a member of the MIT Brain and Cognitive Sciences faculty. “We see that the convergence of lipid metabolism is disrupted, but when you really look more closely at the types of lipid pathways that are disrupted in different types of brain cells, they’re all different.

“I feel that lipid dysregulation may be this very fundamental biology that underlies many of the pathologies that we see,” she said.

The paper’s lead authors are Joel Blanchard, an assistant professor at the Icahn School of Medicine at Mount Sinai who began as a graduate student in Tsai’s lab at MIT, Juna von Meidel and Leila Akai, who are graduate students in Tsai’s lab, and José Dávila Velderrein. , a research group leader at Human Technopole and a former graduate student in the lab of co-author Manolis Kelis, a professor of computer science at MIT.

Many methods of research myelination

Postmortem human brain samples were obtained from the Religious Orders Study and the Rush Memory and Aging Project. The snRNAseq team’s results, a dataset von Meidel made freely available, spanned more than 160,000 individual cells from 11 different types of prefrontal cortex in 32 people — 12 with two copies of APOE3, 12 with one copy of both APOE3 and APOE4, and eight with two APOE4 copies. APOE3/3 and APOE3/4 samples were balanced for Alzheimer’s disease diagnosis, sex, and age. All APOE4/4 carriers had Alzheimer’s disease, and 5 of the 8 were female.

Some results mirrored known Alzheimer’s disease, but other patterns were novel. One in particular showed that oligodendrocytes carrying APOE4 showed greater expression of genes involved in cholesterol synthesis and impaired cholesterol transport. The more copies of APOE4 people had, the greater the effect. This was particularly interesting given the results of a previous analysis by the Tsai and Kelis labs in 2019 that linked Alzheimer’s disease to reduced expression of myelination genes among oligodendrocytes.

Using a variety of techniques to directly examine the tissue, the team saw that in APOE4 brains, aberrant amounts of cholesterol accumulate in cell bodies, particularly in oligodendrocytes, but are relatively lacking around nerve axons.

To understand why, the team used pluripotent stem cells obtained from patients to create laboratory cell cultures of oligodendrocytes engineered to differ only in whether they have APOE4 or APOE3. APOE4 cells again showed severe lipid abnormalities. Specifically, the affected oligodendrocytes stored extra cholesterol in their bodies, showed signs that the extra internal fat was straining organelles called the endoplasmic reticulum that are involved in cholesterol transport, and actually transported less cholesterol to their membranes. Later, when co-cultured with neurons, APOE4 oligodendrocytes failed to myelinate neurons as well as APO3 cells, regardless of whether they carried APOE4 or APOE3 neurons.

The team also noticed that APOE4 carriers had less myelination than APOE3 carriers in postmortem brains. For example, the sheaths around axons that pass through the corpus callosum (the structure that connects the brain’s hemispheres) were markedly thinner in APOE4 brains. The same was true for mice engineered to contain human APOE4 compared to mice engineered for APOE3.

Productive intervention

In an effort to find a potential intervention, the team focused on drugs that affect cholesterol, including statins (which suppress synthesis) and cyclodextrin, which helps transport cholesterol. Statins did not help, but application of cyclodextrin to APOE4 oligodendrocytes cultured in dishes reduced the accumulation of cholesterol in the cells and improved myelination in co-cultures with neurons. Moreover, it also had such effects in APOE4 mice.

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

Tsai said a clear picture is emerging in which intervening to correct cell-type-specific lipid dysregulation could potentially help counter APOE4’s contribution to Alzheimer’s disease.

“What’s interesting is that we saw a way to rescue oligodendrocyte function and myelination in laboratory and mouse models,” Tsai said. “But in addition to oligodendrocytes, we may also need to find clinically effective ways to take care of microglia, astrocytes and the vasculature to really fight the disease.”

In addition to the lead authors, Tsai and Kelis, other contributors to the paper are Hansrudy Mathis, Shawn Davidson, Audrey Effenberger Chiu Chen, Kristen Munner-Smith, Ihab Jahar, Erik Orlund, Michael Bula, Emre Agbas, Aisha Ng, Xueqiao Jiang , Martin Kahn, Christina Blanco-Duke, Nicolas Lavoie, Liwang Liu, Ricardo Reyes, Yuan-Ta Lin, Tak Ko, Léa R’Bibeau, William Ralvenius, David Bennett, and Hugh Cam.

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

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