National Institute of Health

Researchers shed light on how a variant form of a particular gene increases the risk of Alzheimer’s disease.

Apolipoprotein E (ApoE), a protein primarily involved in the metabolism of “lipids” in mammals, is known to be associated with the onset of Alzheimer’s disease (AD). However, it is not clear how exactly it contributes to AD. In a new study, researchers from Korea have now detailed the role of ApoE4, a variant of the ApoE gene, in the development of AD, providing a novel therapeutic target for preventing and treating AD.

Researchers from KNIH have provided novel insights into the mechanism underlying the onset of Alzheimer’s disease (AD) in people with the ApoE4 gene, a variant of the gene known to be a risk factor for AD.

Image credit: Juan Gaertner from Shutterstock.

Over 10 million people above the age of 65 are afflicted with dementia each year worldwide. Among them, about 75% suffer from late-onset Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the abnormal aggregation of the amyloid-beta and tau proteins that cause injury and death of the brain cells.

Despite our best efforts, treating AD remains a difficult endeavor since its cause is still not well understood. However, studies have shown that the occurrence of AD is linked to the presence of a certain ApoE4 gene, a variant form or “allele” of the ApoE gene, which is responsible for the expression of a protein called apolipoprotein E (ApoE). The ApoE protein serves a multitude of roles in the brain, ranging from lipid and glucose metabolism to neuronal signaling. While this is an illuminating find, researchers are still in the dark about how ApoE4 actually leads to AD.

Against this backdrop, a team of researchers from South Korea, led by Dr. Chulman Jo from Korea National Institute of Health, attempted to bridge the knowledge gap in a new study. This study was supported by a fund (2019-NI-086-02) from Research of Korea Disease Control and Prevention Agency, and was published in the journal Scientific Reports.

The team explored how ApoE4 affected the process of “autophagy” in the brains of those carrying the ApoE4 allele. “Autophagy is an intracellular degradation pathway that removes abnormal proteins and maintains protein homeostasis through protein quality control. It is, therefore, important for preventing the occurrence and progression of neurodegenerative diseases,” explains Dr. Jo.

They found that the protein FoxO3a, which controls the expression of genes regulating autophagy, was expressed at significantly lower levels in the brains of ApoE4 carriers compared to those of non-carriers. Furthermore, ApoE4 carriers also showed higher levels of FoxO3a phosphorylation, a process which greatly reduced the activity of FoxO3a, than non-carriers.

“By increasing the expression of genes for autophagy, FoxO3a exerts a protective effect by preventing protein toxicity due to accumulation of misfolded or abnormal proteins. The repression of FoxO3a in ApoE4 carriers would, therefore, lead to a greater accumulation of the pathological tau protein in them, which is what we observed,” says Dr. Hee-Young Sohn, the first author of this research paper.[A1] 

In addition, the team used immunoblotting technique to detect the expression levels of autophagy-related gene products, and found them to be much lower in ApoE4 carriers than in non-carriers. This further supported the hypothesis that the suppression of FoxO3a causes a dysfunction of autophagy.

With these insightful findings, the team is excited about the potential implications of their study. Dr. Jo comments, “Our study is the first to identify a relationship between ApoE4 and FoxO3a on autophagy regulation in the brain. The regulation of the ApoE4 - FoxO3a axis could, therefore, provide a novel therapeutic target for treating AD patients with ApoE4 allele, and, in turn, lead to the design of novel therapies.”

We certainly hope his visions are realized soon!

Reference

About National Institute of Health in Korea

The Korea National Institute of Health (KNIH), one of the major operating components of the Ministry of Health and Welfare, leads the nation’s medical research. Over the past seven decades, the KNIH has made unwavering efforts to enhance the public’s health and innovate biomedical research. The KNIH seeks to eradicate diseases and make people healthier. The KNIH establishes a scientific basis and evidence underlying health policy as well as provides national research infrastructures. We also promote public health research. To this end, we make efforts to enrich a health research environment by granting funds to research projects and keeping our resources, data, and facilities more open and accessible to researchers.

Website: http://www.nih.go.kr/NIH_ENG/

About Dr. Chulman Jo

Dr. Chulman Jo is a senior staff scientist in the Division of Brain Disease Research at the Korea National Institute of Health. His group studies the molecular risk factors for tau pathology in Alzheimer’s disease. From 2010 to 2012, he received his postdoctoral training at Gail Johnson’s lab at Rochester University Medical Center, New York, USA. He has published 40 papers so far with over 900 citations to his credit.

 [A1]We added the full name of the first author here since he is not introduced in the write-up before. Please check if this is okay.