Elucidation of pathophysiological implications of interneuron degeneration in frontotemporal dementia

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08280
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Nagoya City University
• Principal Investigator: Tsuiji Hitomi 名古屋市立大学, 医薬学総合研究院(薬学), 講師 (40455358)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 前頭側頭葉変性症 / 抑制性介在ニューロン

Outline of Final Research Achievements

TDP-43 is an RNA-binding protein important for many aspects of RNA metabolism. Abnormal accumulation of TDP-43 in the cytoplasm of affected neurons is a pathological hallmark of the neurodegenerative diseases frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we analyse age-dependent changes in TDP-43 transgenic mice that displayed impaired memory. We found the accumulation of abundant poly-ubiquitinated protein aggregates in the hippocampus of aged TDP-43 transgenic mice. Intriguingly, the aggregates contained some interneuron-specific proteins such as parvalbumin and calretinin, suggesting that GABAergic interneurons were degenerated in these mice. The abundance of aggregates significantly increased with age and with the overexpression of TDP-43.Our results indicate that the interneuron degeneration occurs upon aging, and TDP-43 accelerates age-dependent neuronal degeneration, which may be related to the impaired memory of TDP-43 transgenic mice.

Free Research Field

病態神経科学

Academic Significance and Societal Importance of the Research Achievements

加齢に伴って抑制性介在ニューロンが変性し死んでいくこと、認知症の一つである前頭側頭葉変性症FTDのモデルマウスではその変性死が加速することを見出した。これは、認知症の初期症状として知られているニューロンの過剰な興奮を説できる可能性がある。