The Microglial Translocator Protein (TSPO) in Alzheimer's Disease Reflects a Phagocytic Phenotype

Overview

Journal Acta Neuropathol

Specialty Neurology

Date 2024 Nov 14

PMID 39540994

Authors

Emma F Garland

Henrike Antony

Laura Kulagowska

Thomas Scott

Charlotte Rogien

Michel Bottlaender

James A R Nicoll

Delphine Boche

Affiliations

Soon will be listed here.

Abstract

Translocator protein (TSPO) is a mitochondrial protein expressed by microglia, ligands for which are used as a marker of neuroinflammation in PET studies of Alzheimer's disease (AD). We previously showed increasing TSPO load in the cerebral cortex with AD progression, consistent with TSPO PET scan findings. Here, we aim to characterise the microglial phenotype associated with TSPO expression to aid interpretation of the signal generated by TSPO ligands in patients. Human post-mortem sections of temporal lobe (TL) and cerebellum (Cb) from cases classified by Braak group (0-II, III-IV, V-VI; each n = 10) were fluorescently double labelled for TSPO and microglial markers: Iba1, HLA-DR, CD68, MSR-A and CD64. Quantification was performed on scanned images using QuPath software to assess the microglial phenotype of TSPO. Qualitative analysis was also performed for TSPO with GFAP (astrocytes), CD31 (endothelial cells) and CD163 (perivascular macrophages) to characterise the cellular profile of TSPO. The percentage of CD68TSPO double-labelled cells was significantly higher than for other microglial markers in both brain regions and in all Braak stages, followed by MSR-ATSPO microglia. Iba1TSPO cells were more numerous in the cerebellum than the temporal lobe, while CD64TSPO cells were more numerous in the temporal lobe. No differences were observed for the other microglial markers. TSPO expression was also detected in endothelial cells, but not detected in astrocytes nor in perivascular macrophages. Our data suggest that TSPO is mainly related to a phagocytic profile of microglia (CD68) in human AD, potentially highlighting the ongoing neurodegeneration.

References

Hamelin L, Lagarde J, Dorothee G, Leroy C, Labit M, Comley R . Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging. Brain. 2016; 139(Pt 4):1252-64. DOI: 10.1093/brain/aww017. View

Boche D, Gordon M . Diversity of transcriptomic microglial phenotypes in aging and Alzheimer's disease. Alzheimers Dement. 2021; 18(2):360-376. PMC: 9059230. DOI: 10.1002/alz.12389. View

Friedman B, Srinivasan K, Ayalon G, Meilandt W, Lin H, Huntley M . Diverse Brain Myeloid Expression Profiles Reveal Distinct Microglial Activation States and Aspects of Alzheimer's Disease Not Evident in Mouse Models. Cell Rep. 2018; 22(3):832-847. DOI: 10.1016/j.celrep.2017.12.066. View

Walker D, Lue L . Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res Ther. 2015; 7(1):56. PMC: 4543480. DOI: 10.1186/s13195-015-0139-9. View

Lyoo C, Ikawa M, Liow J, Zoghbi S, Morse C, Pike V . Cerebellum Can Serve As a Pseudo-Reference Region in Alzheimer Disease to Detect Neuroinflammation Measured with PET Radioligand Binding to Translocator Protein. J Nucl Med. 2015; 56(5):701-6. PMC: 4839390. DOI: 10.2967/jnumed.114.146027. View

Mittelbronn M, Dietz K, Schluesener H, Meyermann R . Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol. 2001; 101(3):249-55. DOI: 10.1007/s004010000284. View

Hamelin L, Lagarde J, Dorothee G, Potier M, Corlier F, Kuhnast B . Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. Brain. 2018; 141(6):1855-1870. DOI: 10.1093/brain/awy079. View

Fan Z, Brooks D, Okello A, Edison P . An early and late peak in microglial activation in Alzheimer's disease trajectory. Brain. 2017; 140(3):792-803. PMC: 5837520. DOI: 10.1093/brain/aww349. View

Butovsky O, Weiner H . Microglial signatures and their role in health and disease. Nat Rev Neurosci. 2018; 19(10):622-635. PMC: 7255106. DOI: 10.1038/s41583-018-0057-5. View

10.

Kamphuis W, Orre M, Kooijman L, Dahmen M, Hol E . Differential cell proliferation in the cortex of the APPswePS1dE9 Alzheimer's disease mouse model. Glia. 2012; 60(4):615-29. DOI: 10.1002/glia.22295. View

11.

Gui Y, Marks J, Das S, Hyman B, Serrano-Pozo A . Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer's disease brains. Brain Pathol. 2019; 30(1):151-164. PMC: 6904423. DOI: 10.1111/bpa.12763. View

12.

Dyer L, Patterson C . Development of the endothelium: an emphasis on heterogeneity. Semin Thromb Hemost. 2010; 36(3):227-35. PMC: 3328212. DOI: 10.1055/s-0030-1253446. View

13.

Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland T . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017; 169(7):1276-1290.e17. DOI: 10.1016/j.cell.2017.05.018. View

14.

Liu B, Le K, Park M, Wang S, Belanger A, Dubey S . In Vivo Detection of Age- and Disease-Related Increases in Neuroinflammation by 18F-GE180 TSPO MicroPET Imaging in Wild-Type and Alzheimer's Transgenic Mice. J Neurosci. 2015; 35(47):15716-30. PMC: 6705465. DOI: 10.1523/JNEUROSCI.0996-15.2015. View

15.

Boche D, Nicoll J . Invited Review - Understanding cause and effect in Alzheimer's pathophysiology: Implications for clinical trials. Neuropathol Appl Neurobiol. 2020; 46(7):623-640. DOI: 10.1111/nan.12642. View

16.

Serrano-Pozo A, Gomez-Isla T, Growdon J, Frosch M, Hyman B . A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol. 2013; 182(6):2332-44. PMC: 3668030. DOI: 10.1016/j.ajpath.2013.02.031. View

17.

Christensen A, Pike C . TSPO ligand PK11195 improves Alzheimer-related outcomes in aged female 3xTg-AD mice. Neurosci Lett. 2018; 683:7-12. PMC: 6436542. DOI: 10.1016/j.neulet.2018.06.029. View

18.

Cosenza-Nashat M, Zhao M, Suh H, Morgan J, Natividad R, Morgello S . Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 2008; 35(3):306-28. PMC: 2693902. DOI: 10.1111/j.1365-2990.2008.01006.x. View

19.

Minett T, Classey J, Matthews F, Fahrenhold M, Taga M, Brayne C . Microglial immunophenotype in dementia with Alzheimer's pathology. J Neuroinflammation. 2016; 13(1):135. PMC: 4890505. DOI: 10.1186/s12974-016-0601-z. View

20.

Nutma E, Fancy N, Weinert M, Tsartsalis S, Marzin M, Muirhead R . Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases. Nat Commun. 2023; 14(1):5247. PMC: 10462763. DOI: 10.1038/s41467-023-40937-z. View