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Hope for vascular cognitive impairment: Ac-YVAD-cmk as a novel treatment against white matter rarefaction

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journal contribution
posted on 2024-05-01, 04:35 authored by Yun-An Lim, Li Si Tan, Wei Thye Lee, Wei Liang Sim, Yang Lv, Maki Takakuni, Satoshi Saito, Masafumi Ihara, Thiruma ArumugamThiruma Arumugam, Christopher Chen, Fred Wai-Shiu Wong, Gavin Stewart Dawe
Vascular cognitive impairment (VCI) is the second leading cause of dementia with limited treatment options, characterised by cerebral hypoperfusion-induced white matter rarefaction (WMR). Subcortical VCI is the most common form of VCI, but the underlying reasons for region susceptibility remain elusive. Recent studies employing the bilateral cortical artery stenosis (BCAS) method demonstrate that various inflammasomes regulate white matter injury and blood-brain barrier dysfunction but whether caspase-1 inhibition will be beneficial remains unclear. To address this, we performed BCAS on C57/BL6 mice to study the effects of Ac-YVAD-cmk, a caspase-1 inhibitor, on the subcortical and cortical regions. Cerebral blood flow (CBF), WMR, neuroinflammation and the expression of tight junction-related proteins associated with blood-brain barrier integrity were assessed 15 days post BCAS. We observed that Ac-YVAD-cmk restored CBF, attenuated BCAS-induced WMR and restored subcortical myelin expression. Within the subcortical region, BCAS activated the NLRP3/caspase-1/interleukin-1beta axis only within the subcortical region, which was attenuated by Ac-YVAD-cmk. Although we observed that BCAS induced significant increases in VCAM-1 expression in both brain regions that were attenuated with Ac-YVAD-cmk, only ZO-1 and occludin were observed to be significantly altered in the subcortical region. Here we show that caspase-1 may contribute to subcortical regional susceptibility in a mouse model of VCI. In addition, our results support further investigations into the potential of Ac-YVAD-cmk as a novel treatment strategy against subcortical VCI and other conditions exhibiting cerebral hypoperfusion-induced WMR.

Funding

This research was supported by grants to FW-SW (grant #1716424003 from A*STAR-AMED) and GSD (grant #MOE2017-T3-1-002 from the Singapore Ministry of Education). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

History

Publication Date

2024-04-17

Journal

PLoS One

Volume

19

Issue

4

Article Number

e0299703

Pagination

20p.

Publisher

PLOS

ISSN

1932-6203

Rights Statement

© 2024 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.