Activation of translocator protein by XBD173 ameliorates cognitive deficits and neuropathology in an Alzheimer’s mouse model

Pradhan, Arpit Kumar (2023): Activation of translocator protein by XBD173 ameliorates cognitive deficits and neuropathology in an Alzheimer’s mouse model. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)

Abstract

One of the most prevalent forms of dementia among elderly patients, Alzheimer's disease (AD) affects millions of people worldwide and brings a huge burden to the individual as well as the global economy. Accumulation of β-amyloid peptide (Aβ) is a major characteristic feature of AD. Previous clinical studies suggest that depression is a common antecedent of AD and may be an early manifestation of dementia, suggesting biological mechanisms that are partly similar in both these disorders. Targeting the molecular mechanism behind these connected disorders can be an excellent therapeutic strategy. The mitochondrial translocator protein (18 kDa) (TSPO) plays an essential role in neurosteroidogenesis and TSPO ligands are neuroprotective in several neurodisorders. We hypothesized that XBD173 since it induces rapid anxiolysis, may have early (neuro) protective effects in AD pathophysiology. Additionally, previous studies concerning XBD173 show a lower side-effect profile compared to benzodiazepines. Both in-vitro electrophysiological recordings, as well as the cognitive performance of the mice, were accessed to unravel the effect of XBD173 on the pathophysiology of AD. First from the CA1-Long Term Potentiation (CA1-LTP) recordings, we observed that 90 min incubation of Aβ1-42 (50 nM) to murine hippocampal slices, prevented the CA1-LTP development after tetanic stimulation of the Schaffer collaterals. Additionally, there was a reduction in the total spine density of CA1 pyramidal neurons. XBD173 (300 nM) restored LTP deficit as well as spine density in the presence of Aβ1-42. XBD173 incubation recovered mushroom and thin spines, as well as overall spine density, as reflected by Imaris dendritic spine rendering. Interestingly, the incubation of XBD173 did not restore the LTP deficit resulting from Aβ1-42 incubation in a global TSPO knockout (KO) mouse model, suggesting a TSPO-mediated action for XBD173. Chronic administration of TSPO-dependent XBD173 (1mg/kg every second day for 3 months) improves the cognitive performance in 9 months ArcAβ (transgenic AD) mice accessed by the water cross maze. Analyzing the brains of these mice showed that chronic XBD173 treatment reduced plaque load (Methoxy-04 staining) and total Aβ1-42 levels (ELISA) in the cortex. Additionally, we found that chronic treatment with XBD173 reduces astrocytic synaptic pruning in the hippocampus and cortex, which in AD mice was exacerbated. Given, the important role of complement proteins in advancing the pathophysiology of AD, we focused on complement protein C1q which acts as an “eat-me” tag for the neurons to be destroyed. We found that astrocytes in transgenic AD mice contain more C1q engulfment compared to the wild-type. Chronic XBD173 treatment reduces this aberrant astrocytic engulfment of C1q tags. It was interesting to observe that amyloid plaques colocalize with C1q aggregates and these C1q aggregates are reduced in XBD173-treated mice compared to their transgenic counterparts. Additionally, we observed that the activation of TSPO by XBD173 in a chronic-treatment model elevates the levels of the neurosteroids including allopregnanolone, dihydrodeoxycorticosterone (DHDOC), and 3ꞵ5α THDOC in the cortex and hippocampus. We further studied whether neurosteroids could potentially be the main players behind the effectiveness of XBD173 treatment in AD. From the CA1-LTP experiment, we found that 3α5α THDOC (100 nM) and 3ꞵ5α THDOC (100 nM), similar to XBD173 (300 nM), restored the LTP deficit in Aβ1-42 treated slices. However, both XBD (300 nM) and 3α5α THDOC (100 nM), could not prevent the CA1-LTP impairments in GABA delta KO mice. These findings highlight a TSPO-mediated increase in neurosteroidogenesis by XBD173, which, upon release, elevates GABAA receptor activity containing the GABA delta subunit. Allopregnanolone (100 nM) prevents the LTP deficits resulting from Aβ1-40 incubation but not Aβ1-42 incubation. Taken together, the present study highlights the beneficial effects of XBD173 against Aβ-derived pathophysiology. Chronic XBD173 treatment improves cognition and appears to have a disease-modifying effect when applied early in the course of AD. This hypothesis is supported by the reduction of soluble Aβ levels, plaque load, and synaptic pruning by XBD173. In conclusion, our work shows that XBD173, in a TSPO-dependent manner provides neuroprotective benefits in a rodent Alzheimer model evident from both the in vitro as well as in vivo behavioral studies. This study paves the way for further advancements in AD treatments and research and provides a possible effective intervention for AD pathophysiology.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Fakultäten: Graduate School of Systemic Neurosciences (GSN)
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 30. November 2023
• 1. Bericht­erstatter:in: Rammes, Gerhard