Joint Research Team between DGIST, Kyungpook National University, and KIOM Discovered Pathological Function of Alzheimer's Disease Risk Factor (APOE4) and Suggested New Treatment Options

- Confirmed the link between cholesterol accumulated in lysosomes and decreased mitochondrial respiration due to the APOE4 genotype and proposed a possible reason that explains a decline in brain function - Research results published in Cell Reports

□ Professor Jin-soo Seo at the Department of Brain Science, Daegu Gyeongbuk Institute of Science and Technology (DGIST; President Young Kuk), revealed changes in the glycolytic function of astrocytes[1] caused by the APOE4 genotype—a strong risk factor for Alzheimer’s disease—and the potential reason behind the changes. Conducting joint research with Professor In-kyu Lee at the School of Medicine, Kyungpook National University and Dr. Young-hoon Ko at the Korea Institute of Oriental Medicine (KIOM), the research team expects these results to contribute to the prevention and development of a therapy for Alzheimer’s disease.


□ The APOE4 genotype is found in approximately 20% of the general population without dementia. Nonetheless, it is observed among more than 50% of patients with Alzheimer’s disease and is known to be one of the key genetic factors contributing to dementia. Accordingly, while the role of APOE4 in Alzheimer’s disease has been studied in various ways, no one has been able to explain why the APOE4 genotype causes brain function to decline in old age.


□ To identify the reason for this effect, a joint research team between DGIST, Kyungpook National University, and KIOM prepared astrocytes from human-derived pluripotent stem cells and conducted research. The results confirmed that the proportion of glycolysis (a metabolic process that degrades glucose without oxygen to gain energy) specifically increased with the APOE4 genotype, and mitochondrial respiration decreased. They also observed that these changes took place as cholesterol was accumulated in lysosomes[2] and damaged mitochondria were not properly degraded. When accumulated cholesterol was removed, it brought the lysosomal function and mitochondrial degradation back to normal.


□ Professor Jin-soo Seo at the Department of Brain Science, DGIST, said, “During early and adult brain development, in which the brain structure and function are rapidly developing, astrocytes often use glycolysis, a process that can provide energy more quickly. As one gets older, however, the brain relies on more efficient mitochondrial respiration. If the APOE4 genotype reduces astrocytes’ mitochondrial respiration, it may have a bigger adverse effect on the brain function in old age than during adulthood. This research confirmed that it would be possible to bring mitochondrial respiration to normal by restoring the lysosomal function. These results are expected to serve as a reference for developing new treatment options in the future.”


□ Meanwhile, this research was funded by the Ministry of Science and ICT’s Mid-Career Researcher Project and Brain Science Original Technology Development Project, the Korea Institute of Oriental Medicine’s Basic Project, the DGIST’s Grand Challenge Research and Innovation Project (P-CoE), and the Ministry of Health and Welfare and Ministry of Science and ICT’s Dementia Overcoming Research and Development Project. This research article, which was prepared by Hye-in Lee—a student in the combined master’s/PhD program at the Department of Brain Sciences, DGIST—and Sook-hee Jo—a postdoctoral researcher (currently, Senior Manager at Illimis Therapeutics)—as the first authors, was published online in Cell Reports, an international journal.

 corresponding author E-mail address : [email protected]

[1] Astrocyte: It refers to a type of neuroglia in the central nervous system, which is found in large amounts in the brain and spinal cord and is shaped like a star. It regulates the biochemical properties of endothelial cells, which make up the blood-brain barrier, provides nutrients to nerve tissues, and plays a crucial role in the regeneration of damaged tissues in the brain and spinal cord.

[2] Lysosome: It refers to an intracellular organelle that contains various hydrolytic enzymes in small lipids and degrades substances entering cells mostly through endocytosis or phagocytosis.

Published: 03 Nov 2023

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