Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)

Shi, Yuan; Cui, Mochen; Ochs, Katharina; Brendel, Matthias; Struebing, Felix L; Briel, Nils; Eckenweber, Florian; Zou, Chengyu; Bánati, Richard B.; Liu, Guo Jun; Middleton, Ryan J.; Rupprecht, Rainer; Rudolph, Uwe; Zeilhofer, Hanns Ulrich; Rammes, Gerhard; Herms, Jochen; Dorostkar, Mario M.

doi:10.1038/s41593-022-01013-9

Cited by 47 publications

(46 citation statements)

References 53 publications

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“…The absence of microglia changes in 3xTgAD.TSPO -/- mice resembles to the unimpaired activation of microglia in TSPO -/- mice in response to neuronal injury 22 and could indicate the relative low function of TSPO in microglia. However, TSPO appears to be required for microglia–spine interactions in response to diazepam 19 , suggesting a role for microglial TSPO later in AD pathology. Considering astrocytes, the lack of difference at 2 months of age and the lack of differences between WT and TSPO -/- mice seem to prove that the reduction in astrocyte reactivity is not innate but is the consequence of the tripartite Aβ-Tau-TSPO functional interactions.…”

Section: Discussionmentioning

confidence: 99%

“…The early increase of TSPO and the fact that its accumulation correlates with that of amyloid plaques, however, suggests a role in the development of the pathology. Previous studies tend to show that the absence of TSPO reduces the reactivity of glial cells and the inflammatory response 20,21,22 . Thus, to determine the function of TSPO in AD, the use of TSPO knockout mice can be very useful 23 .…”

Section: Introductionmentioning

confidence: 97%

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

Ceyzériat

Meyer²,

Bouteldja³

et al. 2022

Preprint

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The 18kDa translocator protein (TSPO) is up-regulated in glial cells in neurodegenerative diseases. In Alzheimer's disease (AD) animal models, TSPO is first overexpressed in astrocytes and then in microglia. However, the precise role of TSPO in the onset and progression of pathology and symptoms characteristic of the disease remains unknown. Here, we report that in the absence of TSPO in 3xTgAD mice the expected disease onset is significantly delayed and a reduction is seen in the hippocampal load of poorly and highly aggregated forms of Tau (-44% and -82%, respectively) and Aβ42 (-25% and -95%, respectively), at 9 months of age. In addition, the astrocyte reactivity was decreased in 3xTgAD.TSPO-/- mice with a reduction in the morphologic complexity and the size of astrocytes in the dorso-dorsal hippocampus and the hilus. Functionally, the absence of TSPO ameliorated the cognitive consequences of adeno-associated virus-induced Tau over-expression in the hippocampus. This suggests that TSPO plays an important role in the active disease progression of AD. TSPO-inhibiting drugs thus merit further exploration as to their potential to reduce the rate of neurodegenerative disease progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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

Ceyzériat

Meyer²,

Bouteldja³

et al. 2022

Preprint

Self Cite

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“…Recognizing the limitations of the available human studies, variation in radioligands, and how radiotracer uptake was measured, 2,141 several TSPO neuroimaging studies in people with HIV found evidence of microglial activation 142‐145 . A recent study demonstrated in mice that long‐term treatment with diazepam accelerated microglia engulfment of synapses and cognitive impairment through TSPO, as the effects were mitigated in TSPO knockout animals 146 …”

Section: Crosstalk With a Microglial‐nigrostriatal Neuroinflammatory ...mentioning

confidence: 99%

“…The result is the activation of gene expression pathways that are neuroprotective and serve to downregulate the pro-inflammatory response as the damaging stimulus is cleared accelerated microglia engulfment of synapses and cognitive impairment through TSPO, as the effects were mitigated in TSPO knockout animals. 146 Importantly, we felt it necessary to first conduct our HIV rodent study without antiretroviral treatment, given some evidence suggesting that specific therapies may worsen neuroinflammation. 2 Seminal studies in the 1980s-1990s using postmortem brain and CSF from HIV-infected people reported on what has been rediscovered during the current COVID19 pandemic as a "cytokine storm".…”

Section: Cross Talk With a MI Crog Lial-nig Ros Triatal Neuroinfl Amm...mentioning

confidence: 99%

Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

Yim

Smith

Brown

2022

Immunological Reviews

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Our understanding that brain microglia display diversity in gene expression depending on developmental age, region, and in the context of health and disease has rapidly increased over the last several years. The advances emerge from the insights of genetic and molecular tools, which permit interrogation at the single-cell level.Microglia are the innate immune cell guardians of the central nervous system responding to infection, injury, or any chronic condition that disrupts normal homeostatic functions. While common to all the former insults is the initiation of an inflammatory response, the exact molecular mechanisms in each context differ and must be defined. Although not without obvious limitations, rodent models

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“…The administration of TSPO‐specific ligand PK 11195 in mice can increase the levels of progesterone and tetrahydrogestrinone in the brain of mice, and reverse the inflammatory response and cognitive impairment caused by LPS 22 . However, recent research has affirmed that long‐term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via TSPO 23 . This suggests that we should be more cautious in using TSPO ligands for the treatment of neurological diseases.…”

Section: Introductionmentioning

confidence: 99%

Peripheral benzodiazepine receptor TSPO needs to be reconsidered before using as a drug target for a pigmentary disorder

et al. 2022

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The peripheral benzodiazepine receptor (TSPO/PBR) is highly conserved among different species but with perplexing biochemical functions. Multiple ligands of TSPO show commendable regulatory activities in lots of biological functions, such as neuro‐protection, cholesterol transport, and so on. These researches support that TSPO may be a potential target for disease treatment and drug development. Previous studies have shown that its ligands benzodiazepines show a satisfactory effect on melanogenic promotion. However, the potential application of TSPO in drug development for pigmentary disorder needs further investigation. In this study, we confirmed the melanogenesis induction of TSPO ligand, Ro5‐4864 in mouse melanoma cell lines, human skin tissue, and zebrafish embryos by inducing melanin synthesis and melanosome transport. Molecular genetics and pharmacological studies showed that TSPO deficiency did not affect melanin production in B16F10 cells and zebrafish embryos, nor did it affect the melanin promotion effect of Ro5‐4864. Whether or not TSPO exists, the expression of lots of melanogenesis‐related proteins, such as TYR, TRP‐1, DCT, Mlph, and Rab27 was upregulated with the Ro5‐4864 administration. These results indicated that Ro5‐4864 induces melanogenesis in a TSPO‐independent manner, which is inconsistent with previous research. This research is a reminder that we need to be very careful during target validation in drug development.

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Long-term diazepam treatment enhances microglial spine engulfment and impairs cognitive performance via the mitochondrial 18 kDa translocator protein (TSPO)

Cited by 47 publications

References 53 publications

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

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

Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

Peripheral benzodiazepine receptor TSPO needs to be reconsidered before using as a drug target for a pigmentary disorder

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