The National Institutes of Health’s National Institute on Aging has awarded Duke Anesthesiology’s Miles Berger, MD, PhD, a five-year, $3.8 million grant for his project titled, “APOE4 Dependent Regulation of CSF Complement Pathway Activation in the Development of Alzheimer's Disease."
"Although we have known for more than 25 years that inheriting an APOE4 allele (a genetic variant) increases Alzheimer’s disease (AD) risk, it is unclear how and why APOE4 increases this risk,” says Berger, associate professor of anesthesiology. “Recent data has raised the possibility that APOE4 may act by increasing the activation of the complement pathway, a set of proteins that are used by immune cells to kill and phagocytose (or eat) bacteria, and that also play a role in ‘killing’ and ‘eating’ connections or synapses between nerve cells in the brain.”
In this project, Berger and his team of investigators will examine whether people who carry the APOE4 allele (either one or two copies of this allele) have increased evidence of complement pathway activation in the fluid that bathes their brain and spinal cord, known as the cerebrospinal fluid (CSF). They will also determine whether CSF complement pathway activation in APOE4 allele carriers is associated with long-term cognitive decline over a 7.5 year period. Lastly, they will determine whether modulating APOE biology in vivo with a peptide that “mimics” the disease-resistant APOE2 allele blocks activation of the complement pathway. This work will be performed using both targeted and unbiased proteomics methods. These methods can precisely measure the levels of proteins in the complement pathway, and can measure the levels of a large percentage of all proteins present in human CSF, respectively.
Overall, Berger’s research will help us understand how and why APOE4 contributes to neurocognitive decline and increased AD risk; it also has the potential to identify proteins or pathways that could be targeted by drugs to prevent Alzheimer’s disease in people that carry an APOE4 allele.
Co-investigators on this project include Dr. Jeffrey Browndyke (Duke Psychiatry), Mary Cooter-Wright (Duke Anesthesiology), Dr. Matt Foster (Duke Proteomics and Metabolomics Core Facility), Dr. Mike Lutz (Duke Neurology), and colleagues in Dr. Beth Stevens’ lab at Harvard/MIT.