BBB impairment factors

 

https://medicalxpress.com/news/2020-06-path-alzheimer-blood-brain-barrier-impairment.html

 

모르는 것

pericyte: multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries and venules throughout the body

astrocyte: They perform many functions, including biochemical support of endothelial cells that form the blood–brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance and a role in the repair and scarring process of the brain and spinal cord following traumatic injuries. 

 

By developing a lab-engineered model of the human blood-brain barrier (BBB), neuroscientists at MIT's Picower Institute for Learning and Memory have discovered how the most common Alzheimer's disease risk gene causes amyloid protein plaques to disrupt the brain's vasculature and showed they could prevent the damage with medications already approved for human use.

About 25 percent of people have the APOE4 variant of the APOE gene, which puts them at substantially greater risk for Alzheimer's disease. Almost everyone with Alzheimer's, and even some elderly people without, suffer from cerebral amyloid angiopathy (CAA), a condition in which amyloid protein deposits on blood vessel walls impairs the ability of the BBB to properly transport nutrients, clear out waste and prevent the invasion of pathogens and unwanted substances.

 the researchers pinpointed the specific vascular cell type (pericytes) and molecular pathway (calcineurin/NFAT) through which the APOE4 variant promotes CAA pathology.

The research indicates that in people with the APOE4 variant, pericytes in their vessels churn out too much APOE protein.  APOE causes amyloid proteins, which are more abundant in Alzheimer's disease, to clump together. Meanwhile, the diseased pericytes' increased activation of the calcineurin/NFAT molecular pathway appears to encourage the elevated APOE expression.

To investigate the connection between Alzheimer's, the APOE4 variant and CAA, Blanchard, Tsai and co-authors coaxed human induced pluripotent stem cells to become the three types of cells that make up the BBB: brain endothelial cells, astrocytes and pericytes. Pericytes were modeled by mural cells that they tested extensively to ensure they exhibited pericyte-like properties and gene expression.

Grown for two weeks within a three-dimensional hydrogel scaffold, the BBB model cells assembled into vessels that exhibited natural BBB properties, including low permeability to molecules and expression of the same key genes, proteins and molecular pumps as natural BBBs. When immersed in culture media high in amyloid proteins, mimicking conditions in Alzheimer's disease brains, the lab-grown BBB models exhibited the same kind of amyloid accumulation seen in human disease.

To pinpoint how APOE4 makes that difference, they engineered eight different versions covering all the possible combinations of the three cell types having either APOE3 or APOE4. When exposed these month-old models to amyloid-rich media, only versions with APOE4 pericyte-like mural cells showed excessive accumulation of amyloid proteins. Replacing APOE4 mural cells with APOE3-carrying ones reduced amyloid deposition. These results put blame for CAA-like pathology squarely on pericytes.

 

 

요즘 보면 pathogensis를 관찰하기 위해 hydrogel에 비슷한 환경을 만들어서 하는 경우가 많은 것 같다. 

Bio-printing이 정말 중요한 것 같다.

 

reference

Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes, Nature Medicine (2020). DOI: 10.1038/s41591-020-0886-4 , www.nature.com/articles/s41591-020-0886-4