Identifing of common mechanisms of depression and cognitive decline associated with systemic diseases and application to treatment

2023 Fiscal Year Final Research Report

• Project/Area Number: 20H03577
• 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: Tottori University
• Principal Investigator: NAKASO Kazuhiro 鳥取大学, 医学部, 教授 (30379648)
• Co-Investigator(Kenkyū-buntansha): 岩田 正明 鳥取大学, 医学部, 教授 (40346367)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: xCT / xc-系 / ミクログリア / グルタミン酸 / 認知症 / うつ症状 / アルツハイマー病 / パーキンソン病

Outline of Final Research Achievements

We investigated the mechanisms of common symptoms, such as cognitive impairment and depression, observed in various systemic and neurological disorders. We focused on the "system xc-/xCT" induced in brain microglia under pathological conditions and the extracellular glutamate released through it. We clarified its involvement in various pathological models. We observed a symptom-reducing effect of genetic deficiency of xCT or chemical xCT inhibitor on vitamin E deficiency (a type of oxidative stress, aging model), Alzheimer's disease model, and Parkinson's disease model. These results suggest that xCT could be a new therapeutic target for cognitive impairment and depression.

Free Research Field

神経内科学，生化学，神経科学，分子生物学

Academic Significance and Societal Importance of the Research Achievements

従来の認知機能障害やうつ症状の病態研究は，疾患ごとの原因に注目しつつ行われてきた．本研究では種々の疾患に共通な症状発現メカニズムの候補として「xc-系/xCT由来のグルタミン酸」に注目し，新規治療標的分子として位置付けた．さらに，この標的分子を制御できる化合物や抗体を得ることができれば，「認知希望障害やうつ症状克服」という社会的ニーズに応えることが可能となる．これは将来的には神経・精神疾患だけでなく，多種多様な疾患に随伴して見られる認知希望障害やうつ症状対策への波及効果が期待出来る．