Cited by 459Neuroinflammation and Neurodegeneration MechanismsPharmacological Receptor Mechanisms and EffectsNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 75 of the 75 references it cites were found in a registry or an index; 14 of the 47 sources its claims cite were checked for support.

Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain

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Cosenza‐Nashat, M., Zhao, M.‐L., Suh, H.‐S., Morgan, J., Natividad, R., Morgello, S., Lee, S. C.·2009·Neuropathology and Applied Neurobiology

Abstract

AIMS: Microglia are involved in neurodegeneration, are prime targets for anti-inflammatory therapy and are potential biomarkers of disease progression. For example, positron emission tomography imaging employing radioligands for the mitochondrial translocator protein of 18 kDa (TSPO, formerly known as the peripheral benzodiazepine receptor) is being scrutinized to detect neuroinflammation in various diseases. TSPO is presumably present in activated microglia, but may be present in other neural cells. METHODS: We sought to elucidate the protein expression in normal human central nervous system, several neurological diseases (HIV encephalitis, Alzheimer's disease, multiple sclerosis and stroke) and simian immunodeficiency virus encephalitis by performing immunohistochemistry with two anti-TSPO antibodies. RESULTS: Although the overall parenchymal staining was minimal in normal brain, endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells were TSPO-positive. In disease states, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes, but the distribution of TSPO varied depending on the disease, disease stage and proximity to the lesion or relation to infection. Staining with the two antibodies correlated well in white matter, but one antibody also stained cortical neurones. Quantitative analysis demonstrated a significant increase in TSPO in the white matter of HIV encephalitis compared with brains without encephalitis. TSPO expression was also increased in simian immunodeficiency virus encephalitis. CONCLUSIONS: This report provides the first comprehensive immunohistochemical analysis of the expression of TSPO. The results are useful for informing the usage of positron emission tomography as an imaging modality and have an impact on the potential use of TSPO as an anti-inflammatory pharmacological target.

Overview

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Written from the paper’s full text.

TL;DR

This study used two anti-TSPO antibodies to map TSPO immunohistochemically in normal and diseased human and macaque CNS. It found that TSPO is minimally expressed in normal brain parenchyma but is upregulated chiefly in microglia and macrophages, and in some hypertrophic astrocytes, in HIV encephalitis, SIV encephalitis, Alzheimer’s disease, multiple sclerosis and stroke.

Key findings

  • In normal brain, overall parenchymal staining was minimal, but TSPO was positive in endothelial and smooth muscle cells, subpial glia, intravascular monocytes and ependymal cells.
  • In disease, elevated TSPO was present in parenchymal microglia, macrophages and some hypertrophic astrocytes; distribution varied by disease, disease stage, proximity to lesion and relation to infection.
  • Quantitative white matter analysis showed significantly increased TSPO in HIV encephalitis versus HIV− and HIV+ groups for both antibodies (Kruskal-Wallis p < 0.001; Dunn pairwise p < 0.001). HIVE average percent area stained ranged from 0.27–1.24% for mAb and 0.01–0.5% for pAb, with the highest observed image at 4.7%; HIV− ranged from 0.02–0.12% (mAb) and 0.03–0.11% (pAb), and HIV+ from 0.01–0.10% (mAb) and 0.01–0.08% (pAb). HIV− and HIV+ did not differ significantly.
  • TSPO expression was also increased in SIV encephalitis; TSPO+ oligodendrocytes were present in the optic tract in one SIVE and the SIV− brain, and TSPO+ hypertrophic astrocytes were noticeably lacking in SIVE.

Methods

  • Immunohistochemistry with two anti-TSPO antibodies—a rabbit polyclonal and a mouse monoclonal—was performed on formalin-fixed, paraffin-embedded brain tissue from HIV− (n=4), HIV+ without encephalitis (n=5) and HIVE (n=10) cases, plus Alzheimer’s disease (n=9), multiple sclerosis and ischemic infarct cases, and macaque brains (SIV− n=1, SIV+ n=1, SIVE n=2).
  • Single- and double-label colorimetric and fluorescent IHC were used with cell markers including CD68, CD45, GFAP, Iba1, HIV-1 p24 and amyloid-β; antibody absorption was performed for the polyclonal antibody.
  • Quantitative image analysis used NIH ImageJ on 20 random 400X white matter fields per case, expressed as percent area stained; groups were compared by Kruskal-Wallis with Dunn’s multiple comparison tests, and antibody agreement was assessed by Spearman correlation.

Limitations

  • The paper states that the antibody absorption experiment was not repeated because peptide cost was prohibitive, and that neuronal staining with the polyclonal antibody remains a conundrum that may be non-specific, though possible TSPO isoforms or related molecules could not be dismissed.
  • The paper notes that cases of conditions other than HIV were not quantitatively analyzed because corresponding normal controls were not available from each site, and that only two SIVE cases were studied, limiting conclusions about the lack of astrocytic staining in SIVE.
  • Evident from the text: group sizes are small, especially HIV− (n=4), HIV+ (n=5) and macaque groups (n=1 each), and much cell-type assessment was semi-quantitative by morphology; the reported Spearman correlation between antibodies was statistically significant but weak (r = 0.08).

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Integrity signals

Registry

Crossref · 10.1111/j.1365-2990.2008.01006.x

Cites

75 of 75 references verified0 citation errors · 0 not checkable

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73 Own result · 13 Own interpretation · 10 No full text of the sources · 8 Partly supported · 6 Own method · 5 No basis given · 2 Supported · 1 Not supported · 1 Sources not found · accuracy not yet measured

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Citations

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  1. Lee SC, 2006, Cytokines and the CNS, 1

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Metadata

Authors
Cosenza‐Nashat, M., Zhao, M. ‐., Suh, H. ‐., Morgan, J., Natividad, R., Morgello, S., & Lee, S. C.
Affiliations
  • Albert Einstein College of Medicine (US)
  • Roswell Park Comprehensive Cancer Center (US)
  • Borough of Manhattan Community College (US)
  • Mount Sinai Hospital (US)
Venue
Neuropathology and Applied Neurobiology
Publisher
Wiley
Published
2009-04-29
Volume
35
Issue
3
Pages
306-328
ISSN
  • 0305-1846 (ISSN-L)
  • 1365-2990
OpenAlex
W1990912256
Cited by
459
References
73
Citations by year
2026: 8 · 2025: 26 · 2024: 29 · 2023: 25 · 2022: 30 · 2021: 60 · 2020: 47 · 2019: 40 · 2018: 41 · 2017: 34 · 2016: 24 · 2015: 25 · 2014: 24 · 2013: 14 · 2012: 12
FWCI
3.56
Type
journal article
Language
en
Open access
Locations
  • Neuropathology and Applied Neurobiology (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • Sanofi
  • City University of New York
  • National Institutes of Health (RO1 MH55477, AI 51519)
  • Center for AIDS Research, University of Washington
  • National Institute of Mental Health (U01MH083545, R01 MH 55477, U24 MH100931, R24MH059724, R01 MH055477, R25 MH080663)
  • National Institute of Allergy and Infectious Diseases (P30-AI-51519, P30AI051519)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacological Receptor Mechanisms and Effects
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
TSPO, translocator protein (TSPO), microglia, macrophages, astrocytes, neuroinflammation, HIV encephalitis, Alzheimer's disease, multiple sclerosis, stroke, white matter, positron emission tomography
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Brain, Brain Diseases, Endothelium, Female, Humans, Macaca mulatta, Macaca nemestrina, Macrophages, Middle Aged, Multiple Sclerosis, Muscle, Smooth, Neurons, Simian Immunodeficiency Virus, HIV Infections, Microglia, Receptors, GABA, Encephalitis, Viral, Stroke

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