TSPO contributes to neuropathology and cognitive deficits in Alzheimer’s disease
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The 18kDa translocator protein (TSPO) is increased in neurodegenerative diseases. In Alzheimer’s disease (AD) animal models, TSPO’s upregulation is detected first in astrocytes, then in microglia. However, the role of TSPO in the pathophysiology and symptoms characteristic of the disease remains unknown. In the human postmortem hippocampus, we show here that TSPO correlated positively with reactive astrocyte-associated genes and negatively with genes involved in glycolytic pathways. In addition, we observed that TSPO deletion in 3 × TgAD mice reversed the reduction in glucose uptake and reduced astrocyte reactivity. We observed a decrease of poorly and highly aggregated forms of Tau (-44% and -82%, respectively) and Aβ42 (-25% and -95%, respectively) at 9 months of age. In 5 × FAD mice, we confirmed the association between TSPO, astrocyte reactivity and Aβ. Functionally, Tau over-expression in the hippocampus induced a memory decline in WT animals, prevented in TSPO−/− mice. Altogether, these data demonstrate that TSPO plays an important role in the active progression of AD. This identifies TSPO as a potential therapeutic target and highlights the importance of astrocyte metabolism in the pathogenesis of the disease.
Date Issued
2025-10-28
Date Acceptance
2025-10-02
Citation
Journal of Neuroinflammation, 2025, 22
ISSN
1742-2094
Publisher
BMC
Start Page
248
Journal / Book Title
Journal of Neuroinflammation
Volume
22
Issue
1
Copyright Statement
© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41152868
PII: 10.1186/s12974-025-03583-4
Subjects
3 × TgAD
Alzheimer’s disease
Astrocytes
Hippocampus
TSPO
Animals
Alzheimer Disease
Humans
Receptors, GABA
Mice
Mice, Transgenic
Hippocampus
Astrocytes
Male
Mice, Knockout
Disease Models, Animal
Mice, Inbred C57BL
Amyloid beta-Peptides
Female
Cognition Disorders
tau Proteins
Aged
Publication Status
Published
Coverage Spatial
England
Article Number
248
Date Publish Online
2025-10-28