Researchers explain how APOE ε4 weakens the blood-brain barrier — ScienceDaily
Researchers at Columbia University have described a mechanism through which the APOE ε4 genetic variant, associated with an increased risk of Alzheimer’s disease, may weaken the brain’s defenses. As ScienceDaily reports, a key role in this process is played by an excess of fibronectin, a protein that accumulates around blood vessels in the brain.
The study results were published in the journal Nature Aging. Scientists combined analyses of human brain tissue and cerebrospinal fluid samples with experiments involving stem cells, three-dimensional vascular cultures, zebrafish, and mice. In mice carrying the human APOE ε4 variant, fibronectin levels in the brain were nearly twice as high as in animals with the common APOE ε3 variant. This was accompanied by signs of increased blood-brain barrier permeability.
How fibronectin affects the brain barrier
The blood-brain barrier separates the bloodstream from brain tissue and regulates the entry of substances into it. Damage to the barrier may allow compounds that would normally be blocked to enter the brain and may also be linked to inflammation.
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The researchers increased the amount of human fibronectin in astrocytes, cells that support the functioning of this barrier. This intervention made the barrier more permeable, while lowering the protein level improved its function. According to the team, excess fibronectin disrupts cell interactions through integrins and the focal adhesion kinase enzyme, which also affects the signaling pathways of the VEGF, HBEGF, and IGF1 growth factors.
A rare mutation as a guide for treatment
Previous work by the same scientists showed that some APOE ε4 carriers have a rare protective mutation in the FN1 gene. According to the researchers’ conclusions, it may limit the accumulation of fibronectin near brain blood vessels and the associated damage.
APOE ε4 is the strongest common genetic risk factor for Alzheimer’s disease; approximately one in five people carries at least one copy. At the same time, having this variant does not mean the disease will inevitably develop. The authors are considering several experimental approaches: preventing fibronectin accumulation, blocking abnormal cellular signals, or restoring growth factor signaling pathways that support interactions between astrocytes and vascular cells. Potential treatments still require further laboratory research, since fibronectin performs important functions in body tissues and wound healing.
