Liere, P. | bioRxiv Science

bioRxiv2023

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

Alzheimers disease (AD) is characterized by the accumulation of {beta}-amyloid peptide (A{beta}). 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 A{beta} 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 (ArcA{beta}) mice. The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcA{beta}) 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 A{beta} 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.

neuroscience↗

bioRxiv2019

Placental neurosteroids shape cerebellar development and social behaviour

Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders 1,2. The placenta is the first functional foetal endocrine organ, but the direct impact of placental hormone loss on foetal brain in late gestation has not been empirically tested. Allopregnanolone (ALLO) is a non-glucocorticoid, progesterone derivative that acts as a positive modulator of GABA-A receptor activity3 with the potential to alter critical GABA-mediated developmental processes 4,5. To directly test the role of placental ALLO, we generated a novel mouse model in which the gene encoding the synthetic enzyme for ALLO (Akr1c14) is specifically deleted in trophoblasts using a tissue-specific Cre-Lox strategy. ALLO concentrations are significantly decreased in late gestation in placenta and brain when placental Akr1c14 is removed, indicating placenta as the primary gestational ALLO source. We now demonstrate that targeted placental ALLO loss leads to permanent changes in brain development in a sex- and regionally-specific manner. Placental ALLO insufficiency led to male-specific cerebellar white matter (WM) abnormalities characterized by excess myelination with increased myelin protein expression, similar to changes reported in boys with autism spectrum disorders (ASD)6,7. Behavioural testing of these mice revealed increased repetitive behaviour and sociability deficits, two hallmarks of ASD, only in male offspring with placental ALLO insufficiency. Notably, a strong positive correlation was seen between the cerebellar contents of myelin basic protein (MBP) and the severity of ASD-like behaviours. A single injection of ALLO during gestation was sufficient to rescue both cerebellar MBP levels and aberrant behaviours. This study reveals a new role for a placental hormone in shaping specific brain structures and behaviours, and suggests that identifying placental hormone insufficiency or preterm loss may offer novel therapeutic opportunities to prevent later neurobehavioural disorders.

neuroscience↗