Nat Med: Revealing ways to solve Alzheimer's blood-brain barrier damage

JUNE 11, 2020 /PRNewswire/ -- By developing a laboratory-designed model of the Human Blood-Brain Barrier (BBB), neuroscientists at MIT's Picower Institute for Learning and Memory have revealed how the most common Alzheimer's risk genes cause amyloid plaques that disrupt the brain's vein systems, and show that they can prevent these damages by having approved drugs for human useAbout 25 percent of people carry a variant of APOE4 of the APOE gene, which increases their risk of developing Alzheimer's diseaseAlmost every alzheimer's patient, even some non-Alzheimer's patients, suffer from brain amyloid vascular disease (CAA), in which amyloid protein is deposited on the walls of blood vessels, impairing the ability of the blood-brain barrier to transport nutrients properly, remove waste, and prevent the invasion of pathogens and harmful substancesIn a new study published June 8 in the journal Nature Medicine, researchers determined that mutations in the APOE4 gene promote caathesis of CAA through specific vascular cell types (weekly cells) and molecular pathways (calcium-toting phosphatase/NFAT)Photo credit: Blanchard etalLi-Huei Tsai, professor of neuroscience at the Picower Institute and director of the Picower Institute, explained that studies have shown that in people carrying APOE4 mutants, the peripheral cells in the blood vessels produce too much APOE proteinAPOE causes amyloid proteins to come together, while amyloid proteins are more abundant in Alzheimer's diseaseAt the same time, the activation of the calcium-modulating neurophosphatase/NFAT molecular pathway in the diseased weekly cells appears to promote an increase in APOE expressionThere are already drugs that can inhibit this pathwayCurrently, they are used to suppress the immune system after transplantationWhen researchers used drugs such as cyclosporine A and FK506 for laboratory-grown blood-brain barriers with APOE4 variants, they accumulated much less amyloid than they would otherly untreated"We found that there is a particular genetic pathway that is different in people who are prone to Alzheimer's disease," said Joel Blanchard, a postdoctoral fellow at The Tsai Laboratory and lead author of the study"By identifying this, we can identify drugs that can change this pathway back to normal and correct the results associated with Alzheimer's disease"To study the link between Alzheimer's disease, APOE4 mutation, and CAA, Blanchard, Tsai, and co-co-users induced human-induced pluripotent stem cells to make them into three types of cells that make up the blood-brain barrier: endothelial cells in the brain, astrocytes, and peripheral cellsWeeks are simulated by fresco cells, which are extensively tested to ensure that they exhibit characteristics and gene expression similar to zhou cellsAfter two weeks of growth in a 3D hydrogel stent, the blood-brain barrier model cells are assembled into blood vessels to show the natural properties of the hemorrhagic brain barrier, including low penetration of molecules, and the expression of key genes, proteins, and molecular pumps that are identical to the natural blood-brain barrier When immersed in high amyloid protein cultures to simulate the brain condition of Alzheimer's disease, laboratory-trained blood-brain barrier models showed the same accumulation of amyloid protein as human diseases After building the BBB model, they tried to test the difference seleaguency in APOE4 Using several measurements, they found that the blood-brain barrier model carrying APOE4 accumulated more amyloid from the culture than the blood-brain barrier model that carried APOE3, a more typical and healthy genetic variant To find out how APOE4 contributed to this difference, they designed eight different versions, covering all possible combinations of three cell types containing APOE3 or APOE4 When these models were exposed to a myaloid-rich media, only the model of cell-like wall cells at 4 weeks of lipoprotein APOE showed excessive amyloid accumulation Replacing Wall Cells carrying APOE4 with APOE3 can reduce amyloid protein deposition These results directly attribute CAA-like pathology to zhou cells To further test the clinical significance of these findings, the team also looked at the expression of APOE in blood vessel strains samples from the prefrontal cortex and the hippocampus in the human brain, both of which have a significant effect on Alzheimer's disease Consistent with the team's laboratory blood-brain barrier model, people who carried APOE4 showed higher levels of gene expression in the vascular system, especially in weekly cells "That's the focus of this paper," said Tsai, a founding member of MIT's Aging Brain Program "It's really cool because it emphasizes the specificity of APOE cell type "Picture source: Nature Medicine Therapeutics? The next step is to determine how APOE4 is overexpressed through weekly cells As a result, the team identified hundreds of transcription factors -- proteins that determine how genes are expressed -- that are regulated differently in cell-like wall cells at weeks APOE3 and APOE They then looked through the list to see what factors affected aPOE expression A group of factors raised in APOE4 cells stand out: they are part of the calcium-modulating neurophosphatase/NFAT pathway They observed similar pathway siphons in weekly cells in human hippocampus samples As part of an investigation into whether the increased signal activity of this pathway led to amyloid protein deposition and increased CAA, they tested cyclosporine A and FK506 because they reduced the activity of the pathway They found that the drug reduced the expression of APOE in weekly cell-like wall cells, thus reducing Apokyloprotein deposits mediated by APOE4 in the blood-brain barrier model They also tested the drug on mice carrying APOE4 and found that the drug reduced apoe expression and amyloid protein accumulation Blanchard and Tsai note that these drugs may have significant side effects, so their findings may not recommend the use of these drugs to treat patients with CAA "Instead, it points to the value of understanding its mechanisms," Blanchard said "It allows people to design a small molecular screening to find more effective drugs with fewer off-target effects (BioValleyBioon.com) References: Study finds path for the addressing Alzheimer's blood-brain barrier regeny of the human blood-brain barrier in vitro reveals a terse of APOE4 in pericytes, Nature Medicine (2020) DOI: 10.1038/s41591-020-0886-4