Quantification of astrocytic synaptic pruning in mouse hippocampal slices in response to ex vivo Aβ treatment via colocalization analysis with C1q

Pradhan, Arpit Kumar; Shi, Qinfang; Tartler, Katharina Johanna; Rammes, Gerhard

doi:10.1016/j.xpro.2022.101687

Cited by 4 publications

(3 citation statements)

References 17 publications

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“…E. Plaque count comparison between Arc Aβ + vehicle (n=5) and Arc Aβ + XBD (n=5) in the cortex (Mann–Whitney U test: Arc Aβ + vehicle: 81.00 (69.50-246.3) vs Arc Aβ + XBD: 41 (36.15-52.50), p= 0.0159). F. C1q puncta count comparison between Arc Aβ + vehicle (n=5) and Arc Aβ + XBD (n=5) in the cortex and hippocampus (Mann–Whitney U test: Arc Aβ + vehicle: 34.33 (30.75-48.00) vs Arc Aβ + XBD: 14 (11–21), p= 0.0079). G. Representative Golgi-Cox stained apical dendrites in the hippocampus for WT, Arc Aβ + vehicle, and Arc Aβ + XBD groups respectively.…”

Section: Resultsmentioning

confidence: 99%

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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

Neumueller

Klug

et al. 2023

Preprint

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Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid peptide (Aβ). There is increasing evidence that depression may precede AD and may be an early manifestation of dementia, suggesting common mechanisms underlying both diseases. Ligands targeting the mitochondrial translocator protein (18 kDa) (TSPO), promote neurosteroidogenesis and may be neuroprotective. Moreover, TSPO is upregulated in AD. 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. We show that XBD173 (emapunil), via neurosteroid-mediated signaling via 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) mice. 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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Section: Resultsmentioning

confidence: 99%

“…The 3D reconstruction of the astrocytes and measurement of synaptic engulfment in the volume of the astrocyte was performed using IMARIS 9.7 (Oxford Instruments, Bitplane) using the protocol as described previously (21). % ROI colocalization measures (proportionally) the amount of synaptic tag engulfed by the entire astrocyte (GFAP) volume.…”

Section: Methodsmentioning

confidence: 99%

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

Pradhan

Neumueller

Klug

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

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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Glia multitask to compensate for neighboring glial cell dysfunction

Beachum,

Salazar,

Nachbar

et al. 2024

Preprint

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SummaryAs glia mature, they undergo glial tiling to abut one another without invading each other’s boundaries. Upon the loss of the secreted neurotrophin Spätzle3 (Spz3),Drosophilacortex glia transform morphologically and lose their intricate interactions with neurons and surrounding glial subtypes. Here, we reveal that all neighboring glial cell types (astrocytes, ensheathing glia, and subperineurial glia) react by extending processes into the previous cortex glial territory to compensate for lost cortex glial function and reduce the buildup of neuronal debris. However, the loss of Spz3 alone is not sufficient for glia to cross their natural borders, as blocking CNS growth via nutrient-restriction blocks the aberrant infiltration induced by the loss of Spz3. Surprisingly, even when these neighboring glia divert their cellular resources beyond their typical borders to take on new compensatory roles, they are able to multitask to continue to preserve their own normal functions to maintain CNS homeostasis.Graphical Abstract

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Quantification of astrocytic synaptic pruning in mouse hippocampal slices in response to ex vivo Aβ treatment via colocalization analysis with C1q

Cited by 4 publications

References 17 publications

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

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

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

Glia multitask to compensate for neighboring glial cell dysfunction

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