Loss of hippocampal synapses in FTLD: autopsy-based study

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K16586
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Aichi Medical University
• Principal Investigator: Riku Yuichi 愛知医科大学, 付置研究所, 助教 (50748382)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 前頭側頭型認知症 / TDP-43 / tau / シナプス

Outline of Final Research Achievements

TDP-43 and tau aggregates are pathologic hallmarks of frontotemporal lobar degeneration (FTLD). It is known that aggregates demonstrate neurotoxicity and facilitate neuronal death. However, we hypothesized synaptic loss to be an earlier phenomenon than neuronal loss. We included consecutively autopsied cases with FTLD, in which postmortem diagnosis of FTLD-TDP or FTLD-tau were confirmed. In results, FTLD-TDP and FTLD-tau cases showed severe loss of axon terminals that were efferent from hippocampal granule cells. Importantly, in FTLD-TDP cases, axon terminal loss of hippocampal granule cells preceded to neuronal loss. By contrast, in the FTLD-tau cases, axon terminal loss was positively correlated with that of neuronal loss for the hippocampal granule cells. The results indicate that axon terminal loss of the hippocampal granule cells precedes to neuronal loss in FTLD-TDP cases, whereas that arises as a consequence of neuronal loss in FTLD-tau cases.

Free Research Field

神経病理

Academic Significance and Societal Importance of the Research Achievements

この研究により、前頭側頭型認知症の早期病変として海馬顆粒細胞の軸索終末が提起された。特にTDP-43に関連した前頭側頭型認知症においては、神経細胞の脱落が起こる前からこの変化が起こることが示唆された。早期治療の標的として、海馬顆粒細胞のシナプス伝達が重要となってゆくと考えられる。このシナプスはグルタミン酸作動性であり、アルツハイマー病で行われているようなコリン作動性シナプスの補充療法とは異なった創薬が必要になり、かつ効果が期待される。