Knockout of TSPO delays and reduces amyloid, Tau, astrocytosis and behavioral dysfunctions in Alzheimer’s disease

Ceyzériat, Kelly; Meyer, Léa; Bouteldja, Farha; Tsartsalis, Stergios; Amossé, Quentin; Middleton, Ryan J.; Liu, Guo Jun; Bánati, Richard B.; Zilli, Thomas; Garibotto, Valentina; Millet, Philippe; Tournier, Benjamin B.

doi:10.1101/2022.03.26.485919

Cited by 3 publications

(7 citation statements)

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“…This facilitating effect of TSPO in increasing the inflammatory response that we demonstrated is corroborated in vivo by the presence of a decrease in the ability of LPS to induce inflammation in animals previously treated with a TSPO antagonist. , Microglia also shows an ameliorating effect of pharmacological TSPO inhibition upon LPS exposure . Such a protective effect of TSPO inhibition has also been hypothesized in various other pathologies (multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease ,, ) and could therefore indicate a pro-inflammatory function of the TSPO.…”

Section: Discussionsupporting

confidence: 80%

“…5,6 Microglia also shows an ameliorating effect of pharmacological TSPO inhibition upon LPS exposure. 54 Such a protective effect of TSPO inhibition has also been hypothesized in various other pathologies (multiple sclerosis, Alzheimer's disease, and Parkinson's disease 7,8,55 ) and could therefore indicate a pro-inflammatory function of the TSPO.…”

Section: Discussionmentioning

confidence: 91%

“…By a cell-type-specific approach, it has been shown that inhibition of STAT3 in the astrocytes induced the same effect, thus clarifying the role of astrocytic STAT3 . In this same idea, the knockout of TSPO in an AD mouse model induces a decrease in astrocytosis and accumulation of abnormal forms of Tau and amyloid . Thus, the environmental deleterious conditions in AD with LPS and Aβ among others may represent the origin of the TSPO upregulation via STAT3.…”

Section: Discussionmentioning

confidence: 94%

“… 7 The TSPO knockout in a mouse model of Alzheimer’s disease induced a decrease in astrocyte reactivity and in pathological markers. 8 These observations suggest the use of TSPO at a therapeutic level. However, in the central nervous system, even if microglia and astrocytes are now recognized as the main source of TSPO, 9 , 10 its role in glial cells is largely unexplored.…”

Section: Introductionmentioning

confidence: 95%

“…The 18 kDa translocator protein (TSPO) is a mitochondrial membrane protein implicated in many essential mitochondria-based physiological processes, including steroidogenesis, cholesterol transport, cellular bioenergetics, mitochondrial respiration, and apoptosis. , In the brain, TSPO is used as an inflammation marker as it is upregulated in pathological conditions such as Alzheimer’s disease or amyotrophic lateral sclerosis. , Previous studies have shown that TSPO ligands showed a decrease in lipopolysaccharide (LPS)-induced inflammation , and a decrease in pathological marks and cell death in a mouse model of Parkinson’s disease . The TSPO knockout in a mouse model of Alzheimer’s disease induced a decrease in astrocyte reactivity and in pathological markers . These observations suggest the use of TSPO at a therapeutic level.…”

Section: Introductionmentioning

confidence: 99%

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18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity

et al. 2023

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An increase in astrocyte reactivity has been described in Alzheimer’s disease and seems to be related to the presence of a pro-inflammatory environment. Reactive astrocytes show an increase in the density of the 18 kDa translocator protein (TSPO), but TSPO involvement in astrocyte functions remains poorly understood. The goal of this study was to better characterize the mechanisms leading to the increase in TSPO under inflammatory conditions and the associated consequences. For this purpose, the C6 astrocytic cell line was used in the presence of lipopolysaccharide (LPS) or TSPO overexpression mediated by the transfection of a plasmid encoding TSPO. The results show that nonlethal doses of LPS induced TSPO expression at mRNA and protein levels through a STAT3-dependent mechanism and increased the number of mitochondria per cell. LPS stimulated reactive oxygen species (ROS) production and decreased glucose consumption (quantified by the [18F]FDG uptake), and these effects were diminished by FEPPA, a TSPO antagonist. The transfection-mediated overexpression of TSPO induced ROS production, and this effect was blocked by FEPPA. In addition, a synergistic effect of overexpression of TSPO and LPS on ROS production was observed. These data show that the increase of TSPO in astrocytic cells is involved in the regulation of glucose metabolism and in the pro-inflammatory response. These data suggest that the overexpression of TSPO by astrocytes in Alzheimer’s disease would have rather deleterious effects by promoting the pro-inflammatory response.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity

et al. 2023

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Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease

Pradhan,

Neumüller,

Klug

et al. 2023

Transl Psychiatry

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Alzheimer’s disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of Aβ on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcAβ). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcAβ) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble Aβ levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.

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The mitochondrial protein TSPO in Alzheimer’s disease: relation to the severity of AD pathology and the neuroinflammatory environment

Garland

Dennett

Lau

et al. 2023

J Neuroinflammation

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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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Knockout of TSPO delays and reduces amyloid, Tau, astrocytosis and behavioral dysfunctions in Alzheimer’s disease

Cited by 3 publications

References 57 publications

18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity

18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity

Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer’s disease

The mitochondrial protein TSPO in Alzheimer’s disease: relation to the severity of AD pathology and the neuroinflammatory environment

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