Pathophysiology and treatment of cognitive impairment in multiple system atrophy.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07452
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Hirosaki University
• Principal Investigator: MIKI YASUO 弘前大学, 医学研究科, 助教 (30709142)
• Co-Investigator(Kenkyū-buntansha): 丹治 邦和 弘前大学, 医学研究科, 助教 (10271800) ; 若林 孝一 弘前大学, 医学研究科, 教授 (50240768) ; 古川 智範 弘前大学, 医学研究科, 助教 (60402369)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 多系統萎縮症 / 記憶障害 / αシヌクレイン / αシヌクレインオリゴマー

Outline of Final Research Achievements

Up to 37% of patients with (multiple system atrophy) MSA may develop cognitive impairment during the disease process. In the present study, we investigated the pathological substrate of cognitive impairment in MSA using a human α-synuclein-inducible MSA mouse model and human brains of patients with MSA. We found that an oligomeric form of α-synuclein was the culprit of cognitive dysfunction in MSA. We then looked for drug candidates to treat MSA in order to delay the progression of the disease and identified two drugs. Drug X was thought to shorten the exposure time of α-synuclein oligomers by accelerating the formation of α-synuclein aggregates. The other drug, Y, delayed the formation of α-synuclein oligomers. Intranasal administration of these drugs significantly improved cognitive impairment in our MSA mouse model. These data suggest that these drugs may be promising candidates for the treatment of MSA.

Free Research Field

神経病理学

Academic Significance and Societal Importance of the Research Achievements

本研究はαシヌクレインオリゴマーがMSAにおける認知機能障害の成因であることを明らかにしたものである。さらに、MSAの認知機能障害を改善する薬剤2剤（X,Y) を同定し、特に薬剤Xは毒性の強いαシヌクレインオリゴマーの暴露時間を減らすことで神経毒性を軽減することを見出した（Tanaka et al. Brain communications 2024)。また、XとYは異常αシヌクレインが脳内に蓄積するレヴィ小体病（パーキンソン病、レヴィ小体型認知症）の治療にも応用できると考えている。