Harnessing brain cortex-derived molecular data to unravel the mechanism underlying the APOE4-associated development of dementia

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03578
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Hiroshima University
• Principal Investigator: Yamazaki Yu 広島大学, 医系科学研究科(医), 講師 (70866243)
• Co-Investigator(Kenkyū-buntansha): 高橋 哲也 広島国際大学, 総合リハビリテーション学部, 教授 (00435942)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: アルツハイマー病

Outline of Final Research Achievements

To elucidate the association between APOE4 and the effector molecule AACT, we successfully achieved the following: 1) construction of a conditional gene knockout system using the Cre-loxp system, 2) creation and characterization of novel humanized APOE mouse models, 3) development of a highly sensitive ELISA for quantification of APOE in human clinical samples, and 4) acquisition of multiple polyclonal antibodies capable of detecting neurodegenerative-related proteins. Although unforeseen events occurred during the course of this research project, they led to the discovery of novel protein X in dissected brains and the creation of the humanized APOE mouse models. By utilizing these tools, we will continue to investigate the molecular pathogenesis of neurological disorders such as Alzheimer's disease.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

アルツハイマー病発症の最も強い遺伝的危険因子はアポリポ蛋白E（APOE）遺伝子であり、APOE4対立遺伝子は劇的に認知症発症リスクを高める一方、APOE2対立遺伝子は保護的に働く。本研究計画により得られた、ヒト化APOEマウスや剖検脳中の新規タンパクXを特異的に認識する抗体は、現在進行中の臨床試験や将来の臨床試験に不可欠な実験病理学的ツールとなり、APOEを標的とする治療法開発に関する新知見を提供する可能性がある。