As part of a search for new genes linked to Alzheimer’s disease, a group of Japanese researchers uncovered a new protein possibly linked to Alzheimer’s disease using CRISPR-Cas9. The study appeared in the FASEB Journal.
In the past, the CRISP-Cas9 system has been used to make modifications to the DNA inside cells and to also measure levels of amyloid-beta in the brain. In the new study, it is the first time that the genetic-based system was utilized to identify changes in the production of amyloid-beta.
In their study, more than 19,000 individual genes were tested for effects on the amount of amyloid-beta. Of the tests, one gene was uncovered to be of interest for researchers: calcium and integrin-binding protein 1 (CIB1).
According to researchers, cells lacking functional CIB1 genes were associated with higher than normal levels of amyloid-beta, however, the reason as to why this occurs remains unclear.
Although CIB1 is not directly linked with the processing of amyloid-beta, CIB1 does stay attached to a protein known as gamma-secretase in healthy cells.
“Amyloid beta protein goes through a multistep process of trimming before it reaches its final form. Under healthy conditions, gamma secretase processes amyloid beta precursors to produce the final amyloid beta protein. That processing activity occurs in an internal compartment within the cell, then gamma secretase moves to the cell’s surface membrane,” the study’s co-authors stated in a news release.
“Additional experiments in mouse cells allowed researchers to track how CIB1 regulates gamma secretase. In healthy cells, CIB1 is not directly involved in gamma secretase’s activity to process amyloid beta, but CIB1 is attached to gamma secretase both in the internal compartment and at the cell surface membrane,” they added.
“In cells without CIB1, gamma secretase remains in the internal compartment inside the cell and does not move to the surface membrane. More time in that internal compartment allows gamma secretase to produce more amyloid beta proteins.”
In the findings, researchers suggest that regulating the location of CIB1 and gamma-secretase may be a pathway for new Alzheimer’s disease therapy.
“We cannot say for certain why CIB1 is increased in late-stage Alzheimer’s disease. What is important is that in both the early and late stages of Alzheimer’s disease, something is abnormal about the regulation of CIB1,” the findings concluded.