2022 Alzheimer's Association Research Grant (AARG)
The chaperone domain BRICHOS in prevention/treatment of Alzheimer's disease
Can a protein that helps determine the structure of other proteins help prevent or treat Alzheimer’s?
Gefei Chen, Ph.D.
Karolinska Institutet
Solna, Sweden
Background
Beta-amyloid is a protein fragment developed from a “parent” molecule called amyloid precursor protein (APP). In Alzheimer’s, beta-amyloid proteins can become “misfolded”and accumulate into clumps, including the hallmark plaques of the Alzheimer’s brain. Misfolded beta-amyloid plaques have been shown to promote brain cell damage and death in dementia.
As with other molecules, proper beta-amyloid folding takes place with the help of proteins called chaperones which assist in folding of proteins into their correct structure. Studies of beta-amyloid folding have identified a chaperone called “Bri2, Chondromodulin-1 and prosurfactant protein C” (or BRICHOS). They found that a specific form of BRICHOS, known as “domain BRICHOS”, may help with correct folding of beta-amyloid and prevent amyloid-related brain cell damage. Moreover, in initial research with mice genetically-engineered to develop high brain levels of beta-amyloid, Dr. Gefei Chen and colleagues found that domain BRICHOS could prevent amyloid-related brain inflammation, changes in behavior, and brain levels of misfolded tau, another hallmark protein linked to Alzheimer’s.
Research Plan
Dr. Chen and colleagues will conduct a larger study of domain BRICHOS and Alzheimer’s. Using bacteria cells grown in a laboratory dish, they will make human beta-amyloid, tau and BRICHOS proteins in the cells. They will then compare how beta-amyloid and tau become folded in cells with and without domain BRICHOS. They will specifically focus on how the presence of domain BRICHOS impacts whether or not correct folding of beta-amyloid takes place. Next, using mice genetically engineered to produce human beta-amyloid and tau, Dr. Chen’s team will inject BRICHOS protein into the mice brain and determine whether domain BRICHOS can prevent memory loss and other forms of cognitive decline.
Impact
The results of this project could clarify our understanding of how misfolded beta-amyloid and tau are produced in Alzheimer’s. They could also lead to novel therapies for disease prevention and treatment.