Mount Sinai researchers have uncovered new details about how APOE4the strongest known genetic risk factor for Alzheimer’s disease, may contribute to brain damage. Two studies published in Cell and cell stem cell show that the gene can damage blood vessels in the brain and promote the accumulation of abnormal proteins associated with neurodegenerative diseases. The findings point to pathological processes that may be reversible and also highlight a new stem cell-derived human brain tissue platform that could accelerate the search for treatments.
Alzheimer’s disease gradually damages memory, thinking and behavior and affects more than 7 million older adults in the United States. Researchers have known for years that blood vessels in the brain deteriorate as Alzheimer’s progresses, especially in people who have APOE4. What has been less clear is why this happens and whether vascular damage directly contributes to the disease. Because of that uncertainty, damage to cerebral circulation has often been treated as a consequence of Alzheimer’s rather than a process that could help drive it.
Mapping how APOE4 damages blood vessels in the brain
For him Cell In a study published September 24, Mount Sinai scientists combined existing data sets to build a single-cell transcriptomic atlas of human brain blood vessels. The resulting map showed patterns of genetic activity in the different cells that create and support the brain’s vascular system, giving researchers a detailed way to examine how APOE4 Contributes to vascular degeneration.
The team discovered that APOE4 It altered the behavior of the pericytes. These cells normally help stabilize small blood vessels and support the blood-brain barrier. In the presence of APOE4However, the pericytes transformed into myofibroblast-like cells that produce scar tissue.
That transformation promoted vascular fibrosis and increased amyloid accumulation around blood vessels. These changes could interfere with blood flow and create conditions that encourage neurodegeneration.
The researchers also found evidence that this process could be reversed. Blocking TGF-β signaling, which plays a role in cell-to-cell communication and tissue remodeling, restored pericyte coverage while reducing fibrosis and amyloid around blood vessels. The researchers reproduced the result in ages APOE4 mice, demonstrating that vascular degeneration associated with APOE4 can be reversed therapeutically.
“Damage to blood vessels in the brain is not simply a late consequence of Alzheimer’s disease; it is a biologically active process caused by APOE4 “These findings reveal new therapeutic targets to preserve vascular function and limit amyloid accumulation,” said corresponding author Joel W. Blanchard, PhD, associate professor of Neuroscience, Stem Cell Biology and Regenerative Medicine at the Icahn School of Medicine at Mount Sinai.
“We show that APOE4 It converts blood vessel support cells into scar-producing cells, causing amyloid, or abnormal protein, to build up around brain vessels. Through our experiments, we were able to block this protein accumulation process, revealing potential new therapeutic treatment options and strategies to protect cerebral circulation in people at high genetic risk for Alzheimer’s disease,” said first author Braxton R. Schuldt, PhD candidate in Neuroscience and researcher in the Blanchard Laboratory at the Icahn School of Medicine at Mount Sinai.
Human mybrains reveal disease mechanisms
An important part of the research was based on miBrains, three-dimensional human brain tissue developed by the Mount Sinai team from induced pluripotent stem cells. The model reproduces important features of human brain tissue, including its network of blood vessels.
The Blanchard lab combined the miBrains findings with preclinical models, postmortem human brain tissue, and transcriptomic data. Each approach helped confirm and expand observations made with the others.
By bringing these systems together, scientists were able to recreate events that occur before the severe vascular abnormalities seen in post-mortem human brain tissue. They could then identify the mechanisms behind those changes and quickly test potential treatments.
APOE4 may also disrupt brain protein clearance
In it cell stem cell study, the researchers used miBrains to explore another effect of APOE4: its role in the accumulation of abnormal proteins associated with neurodegenerative diseases.
Abnormal protein buildup is a defining feature of conditions such as Alzheimer’s and Parkinson’s disease. However, investigating exactly how these deposits form within a living human brain is extremely difficult. The miBrain system offers scientists a way to observe related processes in complex tissues similar to the human brain under laboratory conditions.
miBrains includes all major cell types present in the human brain, including neurons, supporting glial cells, myelin-producing cells, and cells that form blood vessels. Similar to what happens in the human brain, the miBrains that carry APOE4 developed higher amounts of abnormal alpha-synuclein. This protein is most strongly associated with dementia with Lewy bodies and Parkinson’s disease.
Although alpha-synuclein is of great clinical importance, researchers have not fully understood the cellular processes that cause its accumulation.
Cholesterol accumulation impairs the elimination of cellular waste
The experiments revealed that APOE4 It causes cholesterol to build up inside astrocytes, support cells that perform several essential functions to maintain brain health.
That excess cholesterol interfered with the astrocytes’ lysosomal waste removal system. As a result, the cells became less effective at breaking down alpha-synuclein. Instead of being removed, the protein accumulated and spread to neurons, where it contributed to forming harmful deposits.
These findings suggest that cholesterol metabolism within astrocytes, together with lysosomal function, could become important treatment targets for both Alzheimer’s and Parkinson’s diseases.
Using miBrains, the researchers were able to follow the chain of events in a complex tissue similar to the human brain. Their experiments connected APOE4 with lipid accumulation in astrocytes, weaker elimination of alpha-synuclein and formation of toxic protein deposits.
The results point to both lipid metabolism and cellular waste removal systems as potential therapeutic targets in neurodegenerative diseases.
A platform to try personalized treatments
Another advantage of the miBrain system is that researchers can preserve tissue for future experiments.
“A key advance of our technology is that miBrains with predefined cellular compositions and disease-related factors can be cryopreserved,” said Louise Mesentier-Louro, PhD, assistant professor of neuroscience and stem cell biology and regenerative medicine at the Icahn School of Medicine at Mount Sinai and first author of the paper. cell stem cell study. “This capability improves the reproducibility and scalability of complex disease modeling and supports more efficient drug development and validation.”
Mount Sinai researchers are also developing miBrains derived from individual patients, which could eventually allow scientists to investigate how neurodegenerative diseases develop differently from person to person and how patients might respond to particular treatments.
“At Mount Sinai we are creating and cryopreserving patient miBrains,” Dr. Blanchard added. “This will enable personalized studies of how neurodegenerative disease develops and how individuals may respond to therapies. By allowing potential therapies to be tested earlier and more efficiently, the miBrain platform could help close the gap between laboratory discoveries and treatments for a wide range of disorders.”
Study funding
He Cell The study examining vascular degeneration in the brain was supported by the National Aeronautics and Space Administration (80ARC022CA004), the National Institute on Aging of the National Institutes of Health (R01AG089533, UH3NS115064, U54AG090669, T32GM146636), the SWT Foundation, and the CureAlz Fund.
He cell stem cell The study examining abnormal protein buildup in the brain was supported by the National Aeronautics and Space Administration (80ARC022CA004), Aligning Science Across Parkinson’s (ASAP-024297) through the Michael J. Fox Foundation for Parkinson’s Research, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging of the National Institutes of Health. (R01NS114239, UH3NS115064, 1U54AG090669-01, T32AG04968, F31NS13090), the CureAlz Fund and the SWT Foundation.