Elucidation of the repair mechanism of neuronal DNA damage in Alzheimer's disease based on the functional recovery of BRCA1

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03587
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology
• Principal Investigator: Iwata Atsushi 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (40401038)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: アルツハイマー病 / BRCA1 / tau

Outline of Final Research Achievements

The applicant revealed that the accumulation of DNA damage caused by the co-aggregation of tau and BRCA1 in Alzheimer's disease (AD) is the direct cause of neuronal functional decline (Mano, et al., PNAS, 2017). On the other hand, the mechanisms by which DNA damage occurs, how the resulting DNA damage alters genomic DNA, and the DNA repair mechanism of BRCA1 in neurons are unknown, and the following goals were formulated to clarify them.1) Elucidate the mechanisms by which Aβ induces DNA damage.2) To elucidate the effects of Aβ-induced DNA damage on genomic structural changes and gene expression.

Free Research Field

臨床神経内科学

Academic Significance and Societal Importance of the Research Achievements

ADの神経細胞機能の直接的な原因が，BRCA1の機能障害によるDNA傷害の蓄積であるとすれば，tauが蓄積した進行期ADに対して抗Aβ薬は有効ではないことをよく説明する．一方でこの結果は，DNA傷害の蓄積という神経変性の直接的な原因を，BRCA1の機能回復もしくは代償によって治療可能な可能性も示している．このことを検証するため，神経細胞のゲノムDNAにおけるDNA傷害の蓄積の本態は何か，また，このようなゲノムDNA恒常性のリスクに対するBRCA1を中心とした修復機構は何かを問うこととした．