Age-dependent regulation of hippocampal inflammation by the mitochondrial translocator protein in mice

Lai, Kei Onn, Wong, Jia Hui, Tham, Nevin, Fairley, Lauren, Ratnakar Naik, Roshan, Wang, Yulan, Langley, Sarah R. ORCID: https://orcid.org/0000-0003-4419-476X and Barron, Anna M. 2025. Age-dependent regulation of hippocampal inflammation by the mitochondrial translocator protein in mice. Aging Cell

PDF - Accepted Post-Print Version Download (10MB)

Abstract

The mitochondrial translocator protein (TSPO) is a biomarker of inflammation associated with neurodegenerative diseases, widely regarded to be upregulated in the aging brain. Here we investigated the interaction between aging and TSPO immunomodulatory function in the mouse hippocampus, a region severely affected in AD. Surprisingly, we found that TSPO levels were decreased in brain innate immune populations in aging. Aging resulted in a reversal of TSPO knockout transcriptional signatures following inflammatory insult. TSPO deletion drastically exacerbated inflammatory transcriptional responses in the aging hippocampus, whilst dampening inflammation in the young hippocampus. This age-dependent effect of TSPO was linked to NF-kβ and interferon regulatory transcriptional networks. Drugs that disrupt cell cycle and induce DNA-damage such as heat shock protein and topoisomerase inhibitors were identified to mimic the inflammatory transcriptional signature characterizing TSPO-dependent aging most closely. These findings indicate that TSPO plays a protective role in brain aging. This TSPO-aging interaction is an important consideration in the interpretation of TSPOtargeted biomarker and therapeutic studies, as well as in vitro studies which cannot model the aging brain.

Item Type:	Article
Status:	In Press
Schools:	Schools > Biosciences
Publisher:	Wiley
ISSN:	1474-9718
Date of First Compliant Deposit:	5 March 2025
Date of Acceptance:	5 March 2025
Last Modified:	20 Mar 2025 14:45
URI:	https://orca.cardiff.ac.uk/id/eprint/176648

Actions (repository staff only)

Edit Item