The mitochondrial protein TSPO in Alzheimer's disease: relation to the severity of AD pathology and the neuroinflammatory environment.
Alzheimer’s disease
Cerebellum
Human post-mortem
Inflammation
Microglia
Pathology
TSPO
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
14 Aug 2023
14 Aug 2023
Historique:
received:
24
04
2023
accepted:
02
08
2023
medline:
18
8
2023
pubmed:
15
8
2023
entrez:
14
8
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37580767
doi: 10.1186/s12974-023-02869-9
pii: 10.1186/s12974-023-02869-9
pmc: PMC10424356
doi:
Substances chimiques
Mitochondrial Proteins
0
Receptors, GABA
0
TSPO protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
186Subventions
Organisme : Alzheimer's Research UK
ID : ARUK-PhD2019-016
Organisme : Alzheimer's Research UK
ID : ARUK-PhD2019-016
Organisme : Alzheimer's Research UK
ID : ARUK-PhD2019-016
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Efthymiou AG, Goate AM. Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol Neurodegener. 2017;12(1):43.
pubmed: 28549481
pmcid: 5446752
Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS ONE. 2010;5(11): e13950.
pubmed: 21085570
pmcid: 2981526
Yokokura M, Terada T, Bunai T, Nakaizumi K, Takebayashi K, Iwata Y, et al. Depiction of microglial activation in aging and dementia: Positron emission tomography with [(11)C]DPA713 versus [(11)C]( R)PK11195. J Cereb Blood Flow Metab. 2017;37(3):877–89.
pubmed: 27117856
Hamelin L, Lagarde J, Dorothee G, Leroy C, Labit M, Comley RA, et al. 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.
pubmed: 26984188
Rakic S, Hung YMA, Smith M, So D, Tayler HM, Varney W, et al. Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease. Acta Neuropathol Commun. 2018;6(1):88.
pubmed: 30193587
pmcid: 6127939
Franco-Bocanegra DK, George B, Lau LC, Holmes C, Nicoll JAR, Boche D. Microglial motility in Alzheimer’s disease and after Abeta42 immunotherapy: a human post-mortem study. Acta Neuropathol Commun. 2019;7(1):174.
pubmed: 31703599
pmcid: 6842157
Minett T, Classey J, Matthews FE, Fahrenhold M, Taga M, Brayne C, et al. Microglial immunophenotype in dementia with Alzheimer’s pathology. J Neuroinflammation. 2016;13(1):135.
pubmed: 27256292
pmcid: 4890505
Hamelin L, Lagarde J, Dorothee G, Potier MC, Corlier F, Kuhnast B, et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer’s disease. Brain. 2018;141(6):1855–70.
pubmed: 29608645
Lagarde J, Sarazin M, Bottlaender M. In vivo PET imaging of neuroinflammation in Alzheimer’s disease. J Neural Transm (Vienna). 2018;125(5):847–67.
pubmed: 28516240
Jaremko L, Jaremko M, Giller K, Becker S, Zweckstetter M. Structure of the mitochondrial translocator protein in complex with a diagnostic ligand. Science. 2014;343(6177):1363–6.
pubmed: 24653034
pmcid: 5650047
Nutma E, Ceyzeriat K, Amor S, Tsartsalis S, Millet P, Owen DR, et al. Cellular sources of TSPO expression in healthy and diseased brain. Eur J Nucl Med Mol Imaging. 2021;49(1):146–63.
pubmed: 33433698
pmcid: 8712293
Gui Y, Marks JD, Das S, Hyman BT, Serrano-Pozo A. Characterization of the 18 kDa translocator protein (TSPO) expression in post-mortem normal and Alzheimer’s disease brains. Brain Pathol. 2020;30(1):151–64.
pubmed: 31276244
Boche D, Gerhard A, Rodriguez-Vieitez E, Faculty M. Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2019;46(13):2831–47.
pubmed: 31396666
pmcid: 6879435
Chauveau F, Becker G, Boutin H. Have (R)-[(11)C]PK11195 challengers fulfilled the promise? A scoping review of clinical TSPO PET studies. Eur J Nucl Med Mol Imaging. 2021;49(1):201–20.
pubmed: 34387719
pmcid: 8712292
Venneti S, Lopresti BJ, Wiley CA. Molecular imaging of microglia/macrophages in the brain. Glia. 2013;61(1):10–23.
pubmed: 22615180
Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab. 2012;32(1):1–5.
pubmed: 22008728
Lyoo CH, Ikawa M, Liow JS, Zoghbi SS, Morse CL, Pike VW, et al. 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.
pubmed: 25766898
Franco-Bocanegra DK, McAuley C, Nicoll JAR, Boche D. Molecular mechanisms of microglial motility: changes in ageing and Alzheimer’s disease. Cells. 2019;8(6):639.
pubmed: 31242692
pmcid: 6627151
Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82.
pubmed: 22743772
Murabe Y, Sano Y. Morphological studies on neuroglia. VI. Postnatal development of microglial cells. Cell Tissue Res. 1982;225(3):469–85.
pubmed: 6290069
Dyer LA, Patterson C. Development of the endothelium: an emphasis on heterogeneity. Semin Thromb Hemost. 2010;36(3):227–35.
pubmed: 20490975
pmcid: 3328212
Maeda J, Minamihisamatsu T, Shimojo M, Zhou X, Ono M, Matsuba Y, et al. Distinct microglial response against Alzheimer’s amyloid and tau pathologies characterized by P2Y12 receptor. Brain Commun. 2021;3(1):fcab011.
pubmed: 33644757
pmcid: 7901060
International HapMap C. The International HapMap project. Nature. 2003;426(6968):789–96.
Braak H, Braak E, Bohl J, Lang W. Alzheimer’s disease: amyloid plaques in the cerebellum. J Neurol Sci. 1989;93(2–3):277–87.
pubmed: 2556503
Delacourte A, David JP, Sergeant N, Buee L, Wattez A, Vermersch P, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology. 1999;52(6):1158–65.
pubmed: 10214737
Hu W, Wu F, Zhang Y, Gong CX, Iqbal K, Liu F. Expression of Tau pathology-related proteins in different brain regions: a molecular basis of Tau pathogenesis. Front Aging Neurosci. 2017;9:311.
pubmed: 29021756
pmcid: 5623682
Golla SS, Boellaard R, Oikonen V, Hoffmann A, van Berckel BN, Windhorst AD, et al. Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer’s disease patients. J Cereb Blood Flow Metab. 2015;35(5):766–72.
pubmed: 25649991
pmcid: 4420859
Boche D, Nicoll JAR. Invited review: understanding cause and effect in Alzheimer’s pathophysiology: Implications for clinical trials. Neuropathol Appl Neurobiol. 2020;46(7):623–40.
pubmed: 32643143
Mittelbronn M, Dietz K, Schluesener HJ, 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.
pubmed: 11307625
Dos Santos SE, Medeiros M, Porfirio J, Tavares W, Pessoa L, Grinberg L, et al. Similar microglial cell densities across brain structures and mammalian species: implications for brain tissue function. J Neurosci. 2020;40(24):4622–43.
pubmed: 32253358
pmcid: 7294795
Garcia FJ, Sun N, Lee H, Godlewski B, Mathys H, Galani K, et al. Single-cell dissection of the human brain vasculature. Nature. 2022;603(7903):893–9.
pubmed: 35158371
pmcid: 9680899
Dani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R, et al. Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain. 2018;141(9):2740–54.
pubmed: 30052812
Malpetti M, Kievit RA, Passamonti L, Jones PS, Tsvetanov KA, Rittman T, et al. Microglial activation and tau burden predict cognitive decline in Alzheimer’s disease. Brain. 2020;143(5):1588–602.
pubmed: 32380523
pmcid: 7241955
Ceyzériat K, Meyer L, Bouteldja F, Tsartsalis S, Amossé Q, Middleton RJ, et al. Knockout of TSPO delays and reduces amyloid, Tau, astrocytosis and behavioral dysfunctions in Alzheimer’s disease. bioRxiv. 2022. https://doi.org/10.1101/2022.03.26.485919 .
doi: 10.1101/2022.03.26.485919
Li Y, Xia X, Wang Y, Zheng JC. Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease. J Neuroinflammation. 2022;19(1):248.
pubmed: 36203194
pmcid: 9535890
Baik SH, Kang S, Lee W, Choi H, Chung S, Kim JI, et al. A breakdown in metabolic reprogramming causes microglia dysfunction in Alzheimer’s disease. Cell Metab. 2019;30(3):493-507.e7.
pubmed: 31257151
Navarro V, Sanchez-Mejias E, Jimenez S, Munoz-Castro C, Sanchez-Varo R, Davila JC, et al. Microglia in Alzheimer’s disease: activated, dysfunctional or degenerative. Front Aging Neurosci. 2018;10:140.
pubmed: 29867449
pmcid: 5958192
Rentzos M, Zoga M, Paraskevas GP, Kapaki E, Rombos A, Nikolaou C, et al. IL-15 is elevated in cerebrospinal fluid of patients with Alzheimer’s disease and frontotemporal dementia. J Geriatr Psychiatry Neurol. 2006;19(2):114–7.
pubmed: 16690997
Taipa R, das Neves SP, Sousa AL, Fernandes J, Pinto C, Correia AP, et al. Proinflammatory and anti-inflammatory cytokines in the CSF of patients with Alzheimer’s disease and their correlation with cognitive decline. Neurobiol Aging. 2019;76:125–32.
pubmed: 30711675
Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation. 2012;9:179.
pubmed: 22824372
pmcid: 3419089
Kiyota T, Machhi J, Lu Y, Dyavarshetty B, Nemati M, Yokoyama I, et al. Granulocyte-macrophage colony-stimulating factor neuroprotective activities in Alzheimer’s disease mice. J Neuroimmunol. 2018;319:80–92.
pubmed: 29573847
pmcid: 5916331
Tarkowski E, Wallin A, Regland B, Blennow K, Tarkowski A. Local and systemic GM-CSF increase in Alzheimer’s disease and vascular dementia. Acta Neurol Scand. 2001;103(3):166–74.
pubmed: 11240564
Strobel S, Grunblatt E, Heinsen H, Riederer P, Espach T, Meder M, et al. Astrocyte- and microglia-specific mitochondrial DNA deletions levels in sporadic Alzheimer’s disease. J Alzheimers Dis. 2019;67(1):149–57.
pubmed: 30475765
Yamashita U, Kuroda E. Regulation of macrophage-derived chemokine (MDC, CCL22) production. Crit Rev Immunol. 2002;22(2):105–14.
pubmed: 12433129
Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol. 2002;124(1–2):83–92.
pubmed: 11958825
Motta M, Imbesi R, Di Rosa M, Stivala F, Malaguarnera L. Altered plasma cytokine levels in Alzheimer’s disease: correlation with the disease progression. Immunol Lett. 2007;114(1):46–51.
pubmed: 17949824