Understanding Alzheimer’s Disease to Avoid Side Effects of Drugs

WonHee Kim, PhD
Tufts University (Boston, MA)

Mentors

Giuseppina Tesco, MD, PhD
Tufts University (Boston, MA)
Year Awarded:
2019
Grant Duration:
July 1, 2019 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2019021F
Award Type:
Postdoctoral Fellowship
Award Region:
US Northeastern
WonHee Kim, PhD

Impact of Elevated APP on BACE1 Substrates Processing

Summary

Individuals with Alzheimer’s disease (AD) have trouble remembering even simple things, like the name of their family members. AD is generally found in people older than 65 years of age, but some people born with genetic risk factors, such as Down Syndrome and gene mutations causing familial Alzheimer’s disease develop symptoms much earlier. Currently there is no treatment able to prevent or cure AD. Pharmaceutical companies have developed a drug, called BACE inhibitor, that has the potential to prevent and cure AD. However, it is still uncertain whether this drug is safe for AD patients. Our study suggests that this medicine could cause worse side effects in people born with Down Syndrome or carrying a specific genetic mutation causing AD. Therefore, our goal is to better understand AD caused by genetic risk factors, and ultimately find a safe drug treatment for AD patients.

Details

Alzheimer’s disease (AD) is generally found in people older than 65 years of age, though some people born with genetic risk factors, such as Down Syndrome (DS) and AD-causing gene mutations, develop symptoms much earlier.  Since the generation of toxic amyloid beta from amyloid precursor protein (APP) is initiated by the BACE1 enzyme, BACE1 is the prime therapeutic target for AD.  As a result, several BACE inhibitor drugs are currently being tested in clinical trials for AD.  However, very recently, two separate BACE inhibitor trials have been halted due to adverse side-effects, including the worsening of cognitive functions.  Given that BACE1 preferentially cleaves other substrates, over APP, the degree of BACE1 inhibition required to reduce toxic amyloid beta levels may be sufficient to severely impair the processing of other BACE1 substrates, with potential mechanism-based side effects resulting from this relationship between BACE1 and APP.  Consistent with these results, we found that BACE1 inhibitors could cause even more severe mechanism-based side effects in people born with DS, than in non-DS patients. 

In response to these issues, our recent discovery of novel BACE1 substrates will be thoroughly investigated and used to further characterize BACE1 processing, in both mouse and human brain samples.  Moreover, we will use human neurons, derived from DS and familial AD patients-derived induced pluripotent stem cells (iPSCs), due to the limited availability of human samples with genetic mutation and genetically incomplete mouse modeling of DS.  It is our view that an expanded understanding of novel BACE1 substrates and genetic risk factors will ultimately aid the development of an effective therapeutic approach for the safe prevention and treatment of AD, without detrimental, mechanism-based side-effects.

About the Researcher

Dr. WonHee Kim began his pursuit of neurodegenerative diseases, including Alzheimer’s disease, in 2006, during his Ph.D. program in Biomedical Engineering and Biotechnology at the University of Massachusetts at Lowell (UML). He joined Dr. Garth Hall’s Neurodegenerative Disease Research Lab in 2007.  At that time, the initial focus of his research in the field was on the role of tau in AD, using an in-situ lamprey tauopathy model and the M1C cell culture system.  His major finding during his doctoral program was that human tau can be secreted and accumulated from tau-expressing neurons during the course of degeneration, which is associated with the exosome.  After receiving his Ph.D. in 2011, Dr. Kim joined Dr. Giuseppina Tesco’s Alzheimer's disease Research Laboratory, in the Department of Neuroscience, at the Tufts University School of Medicine in 2012.  As a Postdoctoral Scholar in Dr. Tesco’s Lab, he began studying the GGA3 deletion-mediated increase in BACE1 levels resulting in elevated Aβ production, using the 5XFAD mouse model of AD.  This work represented not only a significant shift in his research focus – from tauopathy to amyloid beta peptides and BACE 1 substrates – but provided him with a golden opportunity to embark on an extended period of advanced training in sophisticated experimental research methods, in biochemistry and genomics. 

Personal Story

During my graduation from college, my sister’s mother-in-law, died tragically, following a battle with amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig’s disease.  This incident ultimately led to my academic and professional research path into the field of neurodegenerative diseases. Prior to this point and during my undergraduate years, I planned to pursue biomedical engineering, studying biomedical polymers.  However, shortly after my family’s loss, I embraced opportunities in neurodegenerative disease research within my Biomedical Engineering and Biotechnology doctoral program at the University of Massachusetts at Lowell. There, I soon became passionate about this research area and was particularly fascinated by Alzheimer’s disease (AD), its etiology and progression
over time. 

Through the process of finding my calling in this field, I have developed a deep love and appreciation for the power and potential of intensive, focused scientific research in the study of neurodegenerative diseases.  In my view, this is why the work and ongoing support of the BrightFocus Foundation has been critically important to the development of viable scientific progress in this field.   I would like to express my deepest gratitude to the BrightFocus Foundation donors for their foresight and support. I am truly honored to have this opportunity to be part of such a talented, dedicated, insightful and creative group of researchers who make up the
BrightFocus community.  

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