Researchers at Columbia University examined the effects of APOE ε4 on the blood-brain barrier using brain tissue and cerebrospinal fluid analysis, stem cell-based models, vascular organoids, and preclinical animal models.
APOE ε4 is considered the most common genetic risk factor for Alzheimer's disease. Statistically, approximately one in five people carries it. However, having APOE ε4 does not necessarily mean dementia will develop. Researchers previously discovered a rare mutation in the FN1 gene that reduces fibronectin accumulation and is associated with protection against neurodegeneration in APOE ε4 carriers.
The new work explains why this protective mutation might have this effect: lower fibronectin levels aren't simply associated with a lower risk of disease, they also prevent damage to the blood-brain barrier, according to the university's website.
The results were similar in all the models studied. APOE ε4 increased fibronectin levels and promoted its accumulation around brain blood vessels. In mice with APOE ε4, fibronectin levels in the brain were almost twice as high as in animals with the APOE ε3 variant. The researchers also found signs of a disrupted blood-brain barrier.
The scientists then tested whether fibronectin was the cause of vascular damage or merely associated with it. To do this, they increased the amount of human fibronectin in astrocytes, which are involved in maintaining the blood-brain barrier. This change alone was sufficient to render the barrier permeable.
They later also identified the mechanism of damage. Excess fibronectin transmitted abnormal signals into cells, resulting in disruption of the growth factor system. These signals are essential for the interaction between astrocytes and blood vessel cells and the maintenance of the blood-brain barrier.
The results of the analysis of tissue from people with Alzheimer's disease were consistent with the experimental data.
The authors are exploring several potential treatments and prevention options for neurodegeneration. For example, preventing fibronectin accumulation, blocking unwanted molecular signals, or restoring growth factors necessary for the normal functioning of the blood-brain barrier.
Two previous studies have changed our understanding of the mechanisms by which Alzheimer's disease develops.
