The mitochondrial protein TSPO in Alzheimer’s disease: relation to the severity of AD pathology and the neuroinflammatory environment
The mitochondrial protein TSPO in Alzheimer’s disease: relation to the severity of AD pathology and the neuroinflammatory environment
The 18kD translocator protein (TSPO) is used as a positron emission tomography (PET) target to quantify neuroinflammation in patients. In Alzheimer’s disease (AD), the cerebellum is the pseudo-reference region for comparison with the cerebral cortex due to the absence of AD pathology and lower levels of TSPO. However, using the cerebellum as a pseudo-reference region is debated, with other brain regions suggested as more suitable. This paper aimed to establish the neuroinflammatory differences between the temporal cortex and cerebellar cortex, including TSPO expression. Using 60 human post-mortem samples encompassing the spectrum of Braak stages (I–VI), immunostaining for pan-Aβ, hyperphosphorylated (p)Tau, TSPO and microglial proteins Iba1, HLA–DR and MSR-A was performed in the temporal cortex and cerebellum. In the cerebellum, Aβ but not pTau, increased over the course of the disease, in contrast to the temporal cortex, where both proteins were significantly increased. TSPO increased in the temporal cortex, more than twofold in the later stages of AD compared to the early stages, but not in the cerebellum. Conversely, Iba1 increased in the cerebellum, but not in the temporal cortex. TSPO was associated with pTau in the temporal cortex, suggesting that TSPO positive microglia may be reacting to pTau itself and/or neurodegeneration at later stages of AD. Furthermore, the neuroinflammatory microenvironment was examined, using MesoScale Discovery assays, and IL15 only was significantly increased in the temporal cortex. Together this data suggests that the cerebellum maintains a more homeostatic environment compared to the temporal cortex, with a consistent TSPO expression, supporting its use as a pseudo-reference region for quantification in TSPO PET scans.
Alzheimer’s disease, Cerebellum, Human post-mortem, Inflammation, Microglia, Pathology, TSPO
Garland, Emma F.
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Dennet, Oliver
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Lau, Laurie
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Chatelet, David S.
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Bottlaender, Michel
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Nicoll, James A.R.
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Boche, Delphine
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14 August 2023
Garland, Emma F.
b59c66f2-ac4c-4d8d-823d-687769deccce
Dennet, Oliver
afe4f666-62df-4b12-bae3-8a8ddcc27a6e
Lau, Laurie
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Chatelet, David S.
6371fd7a-e274-4738-9ccb-3dd4dab32928
Bottlaender, Michel
7ec76930-cf42-4f7b-8801-fbb3789eabed
Nicoll, James A.R.
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Garland, Emma F., Dennet, Oliver, Lau, Laurie, Chatelet, David S., Bottlaender, Michel, Nicoll, James A.R. and Boche, Delphine
(2023)
The mitochondrial protein TSPO in Alzheimer’s disease: relation to the severity of AD pathology and the neuroinflammatory environment.
Journal of Neuroinflammation, 20 (1), [186].
(doi:10.1186/s12974-023-02869-9).
Abstract
The 18kD translocator protein (TSPO) is used as a positron emission tomography (PET) target to quantify neuroinflammation in patients. In Alzheimer’s disease (AD), the cerebellum is the pseudo-reference region for comparison with the cerebral cortex due to the absence of AD pathology and lower levels of TSPO. However, using the cerebellum as a pseudo-reference region is debated, with other brain regions suggested as more suitable. This paper aimed to establish the neuroinflammatory differences between the temporal cortex and cerebellar cortex, including TSPO expression. Using 60 human post-mortem samples encompassing the spectrum of Braak stages (I–VI), immunostaining for pan-Aβ, hyperphosphorylated (p)Tau, TSPO and microglial proteins Iba1, HLA–DR and MSR-A was performed in the temporal cortex and cerebellum. In the cerebellum, Aβ but not pTau, increased over the course of the disease, in contrast to the temporal cortex, where both proteins were significantly increased. TSPO increased in the temporal cortex, more than twofold in the later stages of AD compared to the early stages, but not in the cerebellum. Conversely, Iba1 increased in the cerebellum, but not in the temporal cortex. TSPO was associated with pTau in the temporal cortex, suggesting that TSPO positive microglia may be reacting to pTau itself and/or neurodegeneration at later stages of AD. Furthermore, the neuroinflammatory microenvironment was examined, using MesoScale Discovery assays, and IL15 only was significantly increased in the temporal cortex. Together this data suggests that the cerebellum maintains a more homeostatic environment compared to the temporal cortex, with a consistent TSPO expression, supporting its use as a pseudo-reference region for quantification in TSPO PET scans.
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More information
Accepted/In Press date: 2 August 2023
Published date: 14 August 2023
Additional Information:
Funding Information:
We would like to thank Dr Laura Palmer at the South West Dementia Brain Bank (SWDBB), their donors and donor’s families for providing brain tissue for this study. Tissue for this study was provided with support from the BDR programme, jointly funded by Alzheimer's Research UK and Alzheimer's Society. The SWDBB is further supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). We would also like to acknowledge the support of the staff of the Histochemical Research Unit, for their help in performing the staining and validating antibodies, for the Biomedical Imaging unit, David Johnston, Regan Doherty, and David Chatelet for their support in the image acquisition and analysis, and to Iain Hartnell for his help with preparing the MSD assay.
Funding Information:
EFG was supported by a PhD studentship from Alzheimer’s Research UK (ARUK-PhD2019-016) and the slide scanner by the Alzheimer’s Research UK equipment grant (ARUK-EG2015A-4).
Funding Information:
We would like to thank Dr Laura Palmer at the South West Dementia Brain Bank (SWDBB), their donors and donor’s families for providing brain tissue for this study. Tissue for this study was provided with support from the BDR programme, jointly funded by Alzheimer's Research UK and Alzheimer's Society. The SWDBB is further supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). We would also like to acknowledge the support of the staff of the Histochemical Research Unit, for their help in performing the staining and validating antibodies, for the Biomedical Imaging unit, David Johnston, Regan Doherty, and David Chatelet for their support in the image acquisition and analysis, and to Iain Hartnell for his help with preparing the MSD assay.
Publisher Copyright:
© 2023, BioMed Central Ltd., part of Springer Nature.
Keywords:
Alzheimer’s disease, Cerebellum, Human post-mortem, Inflammation, Microglia, Pathology, TSPO
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Local EPrints ID: 481214
URI: http://eprints.soton.ac.uk/id/eprint/481214
ISSN: 1742-2094
PURE UUID: 9f56ec0b-c77b-4813-8865-b4e5c0ae399e
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Date deposited: 18 Aug 2023 16:50
Last modified: 18 Mar 2024 04:00
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Contributors
Author:
Emma F. Garland
Author:
Oliver Dennet
Author:
Laurie Lau
Author:
David S. Chatelet
Author:
Michel Bottlaender
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