Scientists at Mount Sinai discovered that the Alzheimer’s risk gene APOE4 could harm brain blood vessels and undermine the cellular machinery that clears away dangerous proteins. Two reports, published in Cell and Cell Stem Cell, detail how the gene damages blood vessels in the brain while also promoting the buildup of abnormal proteins tied to neurodegenerative disease. The results suggest that these disease processes might be capable of being reversed.
The Blood Vessel Map
The Mount Sinai researchers put together several existing data sets into one cell transcriptomic atlas of blood vessels in the human brain for their Cell study. That map displayed how genes behaved across the cells that form and sustain the brain’s vascular system. The team discovered that APOE4 changed how pericytes worked. Pericytes usually help keep small blood vessels stable and aid the blood-brain barrier.
When APOE4 was present, pericytes shifted into myofibroblast-like cells that produce scar tissue. This change pushed forward vascular fibrosis and caused more amyloid to build up around blood vessels. Stopping TGF-β signaling, a pathway tied to cell communication and tissue remodeling, brought back pericyte coverage while cutting down fibrosis and amyloid. The finding held true when repeated in aged APOE4 mice.
The miBrain Platform
The work depended heavily on miBrains, which are three-dimensional pieces of human brain tissue grown from induced pluripotent stem cells. These models recreate key features of human brain tissue, such as its network of blood vessels. The Blanchard laboratory brought together findings from miBrains alongside preclinical models, postmortem human brain tissue, and transcriptomic data.
The findings from each method confirmed and built upon what was observed through the others. Through recreating the chain of events that precede the serious blood vessel abnormalities seen in postmortem human brain tissue, the researchers pinpointed the underlying mechanisms driving those changes and swiftly put potential remedies to the test.
Protein Cleanup Trouble
The research team behind the Cell Stem Cell study employed miBrains to investigate how APOE4 contributes to the accumulation of abnormal proteins linked to neurodegenerative disease. These accumulations of abnormal proteins characterize conditions like Alzheimer’s and Parkinson’s disease.
The miBrain models contain every major cell type found in a human brain, from neurons to supporting glial cells, myelin-producing cells, and those that form blood vessels. The miBrains engineered to carry APOE4 showed increased levels of abnormal alpha-synuclein, the protein most closely tied to Lewy body dementia and Parkinson’s disease.
Cholesterol Buildup
The trials showed that APOE4 leads to a buildup of cholesterol. This accumulation interferes with how cells get rid of waste, which could be the reason abnormal proteins begin to collect in the first place.
Key Facts
- Studies published in Cell and Cell Stem Cell
- miBrains: three-dimensional human brain tissue from induced pluripotent stem cells
- TGF-β signaling blocked to restore pericyte coverage
- Aged APOE4 mice used to reproduce results
Comparison Table
| Study | Focus | Model |
|---|---|---|
| Cell | Blood vessel damage | Human brain transcriptomic atlas |
| Cell Stem Cell | Protein buildup | miBrains from stem cells |
The Bottom Line
A new path has been opened by the Mount Sinai team. APOE4 may actively harm brain blood vessels, and at least some of that damage can be undone. The change marks a move away from treating vascular damage as merely a consequence of disease toward viewing it as a process that could drive disease itself.
Restoring pericyte coverage and reducing amyloid buildup came from blocking TGF-β signaling. That approach gives the miBrain system a fast method for testing potential treatments before they reach animal trials.
There is evidence pointing toward disease processes that might be turned around, and researchers have described a new human brain tissue system that could help move treatment research forward more quickly. This is encouraging news for people living with Alzheimer’s and Parkinson’s.
Source material: “Alzheimer’s risk gene APOE4 may have a reversible weakness,” ScienceDaily.
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