Summary: When people carry the APOE4 gene associated with Alzheimer’s disease, oligodendrocytes fail to transport fat molecules to wrap the neurons that make brain circuit connections. This myelin deficiency may contribute to the pathology and symptoms of Alzheimer’s disease.
It is well known that carrying one copy of the APOE4 gene variant increases the risk of developing Alzheimer’s disease threefold and two copies approximately tenfold, but the basic reasons why and what can be done to help patients remain largely unknown.
A study published by a team from MIT on November 16 in Nature provides new answers as part of a larger line of research that has demonstrated the consequences of APOE4 cell type by cell type in the brain.
The new study combines evidence from post-mortem human brains, human brain cell cultures in the laboratory and Alzheimer’s model mice to show that when people have one or two copies of APOE4, rather than the APOE3 plus version Common and harmless, cells called oligodendrocytes mismanage cholesterol, failing to transport the fat molecule to wrap up the long, vine-like axonal “wiring” that neurons shoot out to make connections to brain circuitry.
Deficiency of this fatty insulator, called myelin, can contribute significantly to the pathology and symptoms of Alzheimer’s disease, because without proper myelination, communications between neurons are impaired.
Recent studies by the research group, led by Professor Picower Li-Huei Tsai, director of the Picower Institute for Learning and Memory and the Aging Brain Initiative at MIT, have found distinct ways in which APOE4 disrupts the way fat molecules, or lipids, are manipulated by major brain cell types, including neurons, astrocytes, and microglia.
In the new study as well as these, the team identified compounds that appear in the laboratory to correct these various problems, generating potential pharmaceutical-based treatment strategies.
The new study extends this work by not only uncovering how APOE4 disrupts myelination, but also providing the first systematic analysis of major brain cell types using single-nuclear RNA sequencing (snRNAseq) to compare how whose gene expression differs in people with APOE4 compared to APOE3.
“This paper shows very clearly from snRNAseq of postmortem human brains in a genotype-specific manner that APOE4 very distinctly influences different types of brain cells,” said Tsai, a faculty member of Brain and Cognitive Sciences. from MIT.
“We find that the convergence of lipid metabolism is disrupted, but when you look in more detail at the type of lipid pathways disrupted in different types of brain cells, they are all different.
“I think lipid dysregulation might be this very fundamental biology underlying a lot of the pathology 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 work as a postdoctoral fellow at Tsai’s MIT lab, Djuna Von Maydell and Leyla Akay, who are graduate students at the Tsai’s lab, and Jose Davila Velderrain. , research group leader at Human Technopole and former postdoc in the lab of co-corresponding author Manolis Kellis, professor of computer science at MIT.
Many methods to examine myelination
Post-mortem human brain samples came from the Religious Orders Study and the Rush Memory and Aging Project. The team’s snRNAseq results, a dataset that von Maydell has made freely available, encompass more than 160,000 individual cells of 11 different types from the prefrontal cortex of 32 people: 12 with two APOE3 copies, 12 with one copy of each APOE3 and APOE4, and eight with two APOE4 copies.
APOE3/3 and APOE3/4 samples were weighted by Alzheimer’s diagnosis, gender and age. All APOE4/4 carriers had Alzheimer’s disease and 5 out of 8 were women.
Some results reflected known Alzheimer’s pathology, but other patterns were novel. One in particular showed that APOE4-bearing oligodendrocytes exhibited greater expression of cholesterol synthesis genes and disturbances in cholesterol transport. The more APOE4 copies people had, the greater the effect.
This was particularly interesting given the results of an earlier analysis from Tsai and Kellis’ labs in 2019 that linked Alzheimer’s disease to reduced expression of myelination genes among oligodendrocytes.
Using a variety of techniques to look directly at tissue, the team saw that in APOE4 brains, aberrant amounts of cholesterol accumulated in cell bodies, particularly oligodendrocytes, but were relatively lacking around neural axons.
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 had APOE4 or APOE3.
Again, APOE4 cells showed major lipid disruptions. In particular, the afflicted oligodendrocytes stored extra cholesterol in their bodies, showed signs that the extra internal fats were stressing organelles called endoplasmic reticulum that play a role in cholesterol transport, and indeed 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 neurons carry APOE4 or APOE3.
The team also observed that in postmortem brains, there was less myelination in APOE4 carriers than in APOE3 carriers. For example, the sheaths around axons passing through the corpus callosum (the structure that connects the cerebral hemispheres) were significantly thinner in APOE4 brains. The same was true in mice engineered to harbor human APOE4 compared to those engineered to have APOE3.
A productive intervention
Eager to find a potential intervention, the team focused on drugs that affect cholesterol, including statins (which suppress synthesis) and cyclodextrin, which facilitates cholesterol transport. Statins did not help, but application of cyclodextrin to dish-cultured APOE4 oligodendrocytes reduced cholesterol accumulation in cells and improved myelination in co-cultures with neurons. Moreover, it also had these effects in APOE4 mice.
Finally, the team treated some APOE4 mice with cyclodextrin, left others untreated, and put them all through two different memory tests. The cyclodextrin-treated mice performed both tests significantly better, suggesting an association between improved myelination and improved cognition.
Tsai said a clear picture is emerging in which intervention to correct cell-type-specific lipid dysregulations could potentially help counteract APOE4’s contributions to Alzheimer’s pathology.
“It is encouraging that we have seen 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 vasculature to really fight disease.”
Other authors of the article include Hansruedi Mathys, Shawn Davidson, Audrey Effenberger Chi0yu 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 and Hugh Cam.
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Image: Image is credited to Tsai Lab/MIT Picower Institute
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“APOE4 alters myelination via dysregulation of cholesterol in oligodendrocytes” by Li-Huei Tsai et al. Nature
APOE4 alters myelination via dysregulation of cholesterol in oligodendrocytes
APOE4 is the most important genetic risk factor for Alzheimer’s disease.
However, the effects of APOE4 on the human brain are not fully understood, limiting the possibilities of developing targeted therapies for carriers. APOE4 and other risk factors for Alzheimer’s disease.
Here, for more complete information on the impact of APOE4 on the human brain, we performed single-cell transcriptomic profiling of post-mortem human brains of APOE4 carriers compared to non-carriers.
This revealed that APOE4 is associated with widespread changes in gene expression in all cell types of the human brain. Consistent with the biological function of APOE, APOE4 significantly altered signaling pathways associated with cholesterol homeostasis and transport.
Confirming these findings with histological and lipidomic analysis of postmortem human brain, induced pluripotent stem cell-derived cells, and targeted replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes, myelinating cells responsible for isolation and promotion of the electrical activity of neurons.
We show that the altered localization of cholesterol in the APOE4 brain coincides with a reduction in myelination. Pharmacological facilitation of cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mouse.
We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, providing therapeutic opportunities for Alzheimer’s disease.
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