A New Method to Separate Subgroups of Alzheimer's Disease by Measuring sAPPβ in Human Cerebrospinal Fluid

Justyna Dobrowolska Zakaria, PhD
Northwestern University (Chicago, IL)

Co-Principal Investigators

Robert Vassar, PhD
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2022
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2019520S
Award Type:
Standard
Award Region:
US Midwestern
Justyna Dobrowolska Zakaria, PhD

Differentiation of Alzheimer's Disease Subgroups Using sAPPβ and sAPPα as Cerebrospinal Fluid Biomarkers of BACE1 Activity

Summary

Our goal is to measure how quickly an AD patient’s brain makes a protein known as sAPPβ, and compare this to a healthy patient’s brain, to determine if in AD there is more sAPPβ being made than normal. Also, there is increasing evidence that not every patient’s Alzheimer’s disease (AD) has the same cause. So additionally, we want to use sAPPβ, and other proteins such as sAPPα and Aβ, to determine if there are subgroups within AD patients, that might respond in different ways to drugs that target AD.

Details

There is increasing evidence that the cause of Alzheimer’s disease (AD) varies from patient to patient, and this may have contributed to the many failed AD clinical trials that did not take this into consideration. In order to better understand the proposed subtypes of AD, our goal is to determine if, and by how much, β-secretase (BACE1) enzymatic activity is increased in late-onset AD (LOAD) patients and in what subgroups of LOAD the shift toward increased BACE1 processing of Amyloid Precursor Protein (APP) occurs.

Brain accumulation of amyloid-beta (Aβ) peptides plays a critical early role in AD. Cutting of APP by BACE1 produces sAPPβ and this event must occur before Aβ can be made.  We hypothesize that a subgroup of LOAD overproduces Aβ because of increased BACE1 activity. By giving patients a labeled infusion, we can measure the production and clearance rates (kinetics) of any proteins being made at that time. We have incorporated this labeling technique to develop a way to measure the kinetics of sAPPβ (as a biomarker of BACE1 activity), as well as another related protein, sAPPα, in living humans. Our goal is to use these methods to measure these newly generated proteins in patients as a way to determine whether BACE1 activity is higher in LOAD than in cognitively healthy humans. Further, we will study differences in the kinetic rates of sAPPβ and sAPPα within the LOAD population of patients to determine if there are subgroups within AD into which patients could be stratified.

About the Researcher

Dr. Zakaria received her B.S. degree in Biology in 2006 from Creighton University and her Ph.D. in Neurosciences in 2013 from Washington University in St. Louis.  Throughout her undergraduate and graduate studies, Dr. Zakaria studied the processing of Amyloid Precursor Protein (APP) in the context of Alzheimer’s disease. After completing her doctoral studies, Dr. Zakaria started her first post-doctoral research project in the Department of Neurosurgery at Washington University, under Dr. Jeffrey Leonard.  During the course of this project, Dr. Zakaria moved with the Leonard lab to Nationwide Children’s Hospital. Her focus for the two years of this project was the microRNA expression in Glioblastoma Multiforme brain tumors in the pediatric setting. In 2015, Dr. Zakaria started a second post-doctoral training position in the laboratory of Dr. Robert Vassar at Northwestern University, focusing once again on AD. She was appointed as a research assistant professor in 2018 at Northwestern’s Department of Neurology. The scope of her research since joining Northwestern four year ago has been APP processing in the context of AD in humans.  She has been collaborating on this project with her former doctoral advisor, Dr. Randall Bateman. During her doctoral training, Dr. Zakaria developed methods for measuring the kinetics of sAPPβ and sAPPα in healthy humans using the highly sensitive stable isotope labeling kinetics/mass spectrometry methods that were later included in a patent. She further developed methods to measure kinetics of these proteins, as well as Aβ, in rhesus monkeys treated with a BACE1 inhibitor in an effort to study how APP processing by BACE1 was modified in a therapeutic setting.  Additionally, Dr. Zakaria also described the phenomenon of human circadian patterns of APP in humans during her time at Washington University. Since joining Northwestern, Dr. Zakaria has used the breadth of expertise she gained while working with Dr. Bateman, to develop methods to measure human sAPPβ and sAPPα kinetics in the setting of AD in an effort to stratify the AD population. In 2017 Dr. Zakaria was awarded the Outstanding Young Investigator Award by the Alzheimer’s Drug Discovery Foundation.  In 2018 she was the Postdoc Poster Competition Winner at Brain Research Foundation's 18th Annual Neuroscience Day and a Postdoc Poster Competition Finalist at the Alzheimer’s Association International Conference.

Personal Story

As a young girl, my initial inspiration for becoming a research scientist was my father, who is a mathematician. However, I was more inclined to study living organisms and how they work, so I decided to major in Biology instead. While at Creighton University, I was given the opportunity to work in the research laboratories of two women scientists, Dr. Cindy Gibson and Dr. Laura Bruce. These two proved to be my earliest mentors in navigating research in the academic setting.  It was while working with Dr. Gibson that I first learned the basics of AD using a mouse model, and most importantly, I learned that this field of study still had a lot of unknowns. Thus my earliest introduction to the protein APP and its role in AD was 15 years ago. My transition to graduate school at Washington University was very smooth with respect to the continuation of my study of APP processing.  I joined the laboratory of Dr. Randall Bateman and in addition to learning new methods of experimentation, he gave me the opportunity to go with him to the clinic to watch him evaluate his AD patients and speak with their caregivers. This experience really opened my eyes to the true impact the disease I was studying had on families. I realized quickly that with the aging population and no effective therapies, the number of affected individuals would keep increasing, and this would leave more and more families devastated by this awful disease. I became worried that it would eventually impact my parents and my other loved ones who were entering their senior years. This human impact is what kept me going throughout my graduate studies.  I felt I could provide some valuable pieces to the puzzle of AD, and this is ultimately the reason I returned to the AD field after the couple years I spent in my first post-doctoral training studying brain tumors.  I am incredibly grateful to the research participants (many of whom are AD patients) without whom this research project would not be possible and to Brightfocus donors whose support is allowing me to continue on this mission to help finish the puzzle that is AD.

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