NEW YORK – The National Institutes of Health have granted $4.8 million to researchers at the Gladstone Institutes to study how apolipoprotein E4 is implicated in Alzheimer's Disease.
The funding is for the first year of a five-year grant from the National Institute of Aging that will use proteomic, genetic, and gene-editing approaches.
"ApoE4 dramatically rewires cellular pathways in neurons and impairs their function," Robert Mahley, president emeritus at the Gladstone Institutes and the grant's principal investigator, said in a statement. "Our goal is to understand how this rewiring occurs and identify potential new treatment strategies to negate the detrimental effects."
The team will begin by using affinity purification mass spectrometry (AP-MS) to determine which proteins in a mouse-derived neuronal cell interact with apoE4 fragments. Then, they will perturb the expression of some of those proteins in human induced pluripotent stem cells, using CRISPR interference or activation, to try to reverse apoE4's harmful effects.
One of the forms of apolipoprotein 4, apoE4 and its gene variant are found in approximately one quarter of all people, but two-thirds of Alzheimer's patients. Approximately 5.8 million Americans are living with Alzheimer's, according to a 2019 report from the Alzheimer's Association.
"ApoE4 is associated with impaired mitochondrial respiration, neurite outgrowth and neurotoxicity," the researchers wrote in their grant abstract. But they noted these effects "can be reversed by apoE4 structure correctors that convert apoE4 to an apoE3-like conformation, thus preventing neurotoxic fragment generation and neurodegeneration."
The project will also use additional proteomic techniques developed in the lab of Gladstone Senior Investigator Nevan Krogan as well as transcriptome profiling.
"By the end of the project, we hope to narrow down our list to just a few target genes or proteins that protect or restore neuronal health when we activate or inhibit them in live mice with the apoE4 gene," Danielle Swaney, mass spec facility director at Gladstone, said. "They could then be explored as potential targets for Alzheimer's treatment in humans."