How Autophagy Recognizes and Degrades Alzheimer’s Disease-Causing Amyloids in the Brain

Congcong He, PhD
Northwestern University (Chicago, IL)

Collaborators

Robert Vassar, PhD
Northwestern University (Chicago, IL)
Year Awarded:
2018
Grant Duration:
July 1, 2018 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2018100S
Award Type:
Standard
Award Region:
US Midwestern
Congcong He, PhD

Mechanisms of Autophagic Regulation of Aβ Metabolism Against Alzheimer’s Disease

Summary

Autophagy, the pathway a brain cell uses to dispose of damaged structures inside the cell, is impaired in Alzheimer’s disease (AD). Brain cells produce a toxic form of amyloid beta (Aβ) peptide, a toxic protein that appears to help cause AD. Our research will show how activated autophagy can recognize and clear amyloids in different types of brain cells, and how to increase the activity of this pathway to accelerate the disposal of amyloids. 

Details

The goal of our research is to understand how autophagy, a protein degradation pathway, regulates Aβ metabolism and neuronal inflammation in the brain, and to study whether autophagy-modulating compounds can be used as promising therapeutics against Alzheimer’s disease (AD). The accumulation of Aβ proteins in the brain is the major hallmark of AD. Although many therapeutic efforts have been made to target Aβ production or aggregation, no effective therapies are available so far to cure AD. We propose that AD is a degenerative condition caused by an imbalance of protein production and protein degradation, and we are very interested in testing the idea that augmenting the capacity of protein degradation reduces amyloid load, and amyloid-induced inflammation and cellular dysfunction. We thus focus on autophagy, a key “self-eating” pathway that has evolved in brain cells to get rid of damaged or toxic proteins. Impairment of autophagy has been observed during AD pathogenesis. Using new transgenic mouse model systems that show high or low autophagy levels, we are dedicated to investigating how the autophagy machinery recognizes amyloids and regulates amyloid metabolism in neurons and microglial cells in the brain, and whether pharmacologically upregulating autophagy is beneficial for restoration of cognitive functions in AD. Particularly, to specifically study the effects of autophagy in AD, we designed a drug screen for novel brain-penetrable autophagy inducers from small-molecule and natural compound libraries and identified lead compounds that can induce autophagy in the brain and restore memory in an AD mouse model. When completed, our study will reveal new mechanisms of protein degradation pathways in memory improvement, and deliver new lead compounds for the development of AD drugs. 

About the Researcher

Dr. Congcong He is an assistant professor in the Department of Cell and Molecular Biology of Feinberg School of Medicine at Northwestern University. She obtained her undergraduate degree in biological sciences from Zhejiang University in China in 2004, and her PhD degree in cell biology from the University of Michigan (Ann Arbor) in 2009. She then received postdoctoral training focusing on protein degradation in mammalian physiology at the University of Texas Southwestern Medical Center in Dallas, before she established her own laboratory in 2013. Dr. He’s research interest is to understand how autophagy, a protein clearance pathway, regulates metabolism, neurodegeneration, and animal behavior using Alzheimer’s disease mouse models. Her team is in active collaboration with Dr. Robert Vassar’s lab at Northwestern University. Dr. He discovered several new mutations in autophagy genes that modulate the trafficking and metabolism of amyloids, and laid the foundation work on the role of autophagy in the regulation of memory and neuronal function in Alzheimer’s animals. The long-term goal of her laboratory is to fully understand the role and mechanism of the protein degradation pathways in neuronal regulation, and to demonstrate how to modulate autophagy to treat Alzheimer’s disease.

Personal Story

At a young age, I learned that aging is an inevitable process for everybody in the world. After witnessing elder family members developing signs of dementia, which reduced not only their quality of life, but also the well-being of the whole family, I realized that having a “healthy aging” process is fortunate and important for both the elderly and the society. Alzheimer’s disease (AD) is the primary cause of memory loss and dementia in the elderly populations. Thus, I am motivated to understand the mechanisms of the disease, and based on the mechanism to develop a potential cure. With recent progress made by many researchers and my own lab, I believe it is an exciting and hopeful era to pursue AD research. My lab has developed the expertise, techniques, and mouse models to resolve important questions in the AD field.

Particularly, it has been puzzling how intracellular degradation (autophagy) regulates the pathogenesis of AD. If our study is successful, we will reveal whether autophagy, and certain proteins involved in autophagy, represent new druggable targets in AD. Using different AD mouse models, we hope to demonstrate the novel mechanism and therapeutic potential of autophagy-modulating compounds in the prevention of AD and restoration of memory.

As an early career scientist in AD research, I am very grateful to the BrightFocus Foundation and the donors for the generous support. The funding allows me, and my team, to carry out this research direction, and to transform a pilot idea into new translatable findings and potential treatment options in AD.

Don't miss out.
Receive research updates, inspiring stories, and expert advice
Please enter your first name.
Please enter your last name.
Keep me informed about: *
Please select at least one.
You must select at least one disease category.