Alzheimer's Gene APOE4 Damages Brain Blood Vessels, and Mount Sinai Says It May Be Reversible
Two studies in Cell and Cell Stem Cell show the gene turns vessel-support cells into scar-forming ones and chokes the cell's waste-disposal system. Blocking one signal undid part of the damage in lab models and mice.
The strongest known genetic risk factor for Alzheimer's disease may do its harm in a way scientists can reverse. Two new studies from Mount Sinai researchers, published in the journals Cell and Cell Stem Cell, show that the APOE4 gene actively damages blood vessels in the brain and also disables the cellular system that clears out harmful proteins.
Carrying one copy of APOE4 raises a person's risk of Alzheimer's, and two copies raise it considerably more. For years the gene has been studied mainly through its effects on neurons and on the amyloid plaques that characterize the disease. The new work shifts attention to the brain's plumbing.
In the first study, in Cell, the team built a single-cell atlas of human brain blood vessels and combined it with lab-grown brain tissue models known as miBrains and with aged mice that carry APOE4. They found that APOE4 causes pericytes, the cells that wrap small vessels and help maintain the blood-brain barrier, to turn into scar-forming cells that resemble myofibroblasts. Those cells promoted fibrosis of the vessel walls and allowed more amyloid to build up around the vessels.
Then the researchers tried to undo it. When they blocked a cellular signaling pathway known as TGF-beta, pericyte coverage of the vessels was restored and both the fibrosis and the vascular amyloid dropped, in the tissue models and in mice. "Damage to the brain's blood vessels is not simply a late consequence of Alzheimer's disease; it is a biologically active process caused by APOE4 that may be reversible," said Dr. Joel Blanchard, a senior author of the work.
The second study, in Cell Stem Cell, used miBrain models carrying the APOE4 variant to look at alpha-synuclein, the protein that clumps in Parkinson's disease and in some forms of dementia. APOE4 caused cholesterol to pile up inside astrocytes, the star-shaped support cells of the brain. That clogged the astrocytes' lysosomes, the compartments that break down waste, and left them unable to degrade alpha-synuclein. The protein then aggregated into toxic clumps.
Together, the studies point to two possible targets for drugs: lipid metabolism inside astrocytes and TGF-beta signaling in blood vessels. The work was funded by the National Institutes of Health, NASA, the Michael J. Fox Foundation, the CureAlz Fund and the SWT Foundation.
The results come with limits that the authors acknowledge. The reversal was shown in lab-grown tissue and in mice, not in people, and TGF-beta is involved in many normal body processes, so blocking it broadly could carry risks. No treatment based on the findings has been tested in patients.
Still, the findings suggest that the vascular damage seen in many people who carry APOE4 may not be a one-way process. If drugs can safely restore the brain's vessels, it could open a new route against Alzheimer's and related diseases, alongside the antibody drugs that clear amyloid.
