Apolipoprotein ε7 allele in memory complaints: insights through protein structure prediction

Abstract

Young Chul Youn,1,* Yong Kwan Lim,2,* Su-Hyun Han,1 Vo Van Giau,3 Mi-Kyung Lee,2 Kwang-Yeol Park,1 SangYun Kim,4,5 Eva Bagyinszky,3 Seong Soo A An,3 Hye Ryoun Kim2 1Department of Neurology, 2Department of Laboratory Medicine, Chung-Ang University College of Medicine, Seoul, 3College of BioNano Technology, Gachon BioNano Research Institute, Gachon University, 4Department of Neurology, Seoul National University Bundang Hospital, 5Department of Neurology, Seoul National University College of Medicine, Seongnam, South Korea *These authors contributed equally to this work Purpose: APOE ε7 gene is a rare mutant form of APOE ε3. The mutation occurs in the lipid-binding domain of APOE. Based on the protein’s structure, APOE ε7 is expected to function in lipid and β-amyloid metabolism, similar to APOE ε4. However, unlike that for APOE ε4, the mechanisms responsible for Alzheimer’s disease (AD) cases associated with APOE ε7 expression have not been elucidated. The present study aims to investigate the association between APOE ε7 expression and cognitive impairment. Methods: APOE was sequenced in DNA samples collected from 344 memory-complaint patients who visited the memory clinic, and from 345 non-memory-complaint individuals from the health promotion center. The protein structures of ApoE3, ApoE4, and ApoE7 were predicted. Results: Three ε3/ε7 heterozygote individuals who were all classified under the memory-complaint group were identified. Of these, two subjects were clinically diagnosed with AD with small vessel disease, and the remaining individual was diagnosed with subjective cognitive impairment. This study predicted the protein structures of ApoE3, ApoE4, and ApoE7 and determined the three-dimensional structure of the carboxy terminus of ApoE7, which participates in an electrostatic domain interaction similar to that of APOE ε4. APOE K244 or K245 mutations for APOE ε7 were not found in the Korean reference genome database, which contains information (http://152.99.75.168/KRGDB/browser/mainBrowser.jsp) from 622 healthy individuals. Conclusion: As verified by the results of structural prediction, APOE ε7 could serve as another risk factor for cognitive impairment and is particularly associated with vascular disease. However, additional studies are required to validate the pathogenic nature of APOE ε7. Keywords: apolipoprotein structure, Alzheimer’s disease, vascular cognitive impairment, small vessel disease

Keywords

• Apolipoprotein structure
• Alzheimer’s disease
• vascular cognitive impairment
• small vessel disease