Therapeutic benefits of central LH receptor agonism in the APP/PS1 AD model involve trophic and immune regulation and reproductive status dependent

Biochim Biophys Acta Mol Basis Dis. 2024 Apr 21:167165. doi: 10.1016/j.bbadis.2024.167165. Online ahead of print.ABSTRACTThe mechanisms that underly reproductive hormone effects on cognition, neuronal plasticity, and AD risk, particularly in relation to gonadotropin LH receptor (LHCGR) signaling, remain poorly understood. To address this knowledge gap and clarify the impact of circulating steroid hormones the therapeutic effects of CNS LHCGR activation, we delivered the LHCGR agonist human chorionic gonadotropin (hCG) intracerebroventricularly (ICV) and evaluated functional, structural, plasticity-related signaling cascades, Aβ pathology, and transcriptome differences in reproductively intact and ovariectomized (OVX) APP/PS1 AD female mice. Here we demonstrate that CNS hCG delivery restored function to wild-type levels only in OVX APP/PS1 mice. Spine density was increases in all hCG treated groups independently of reproductive status. Notably, increases in BDNF signaling, like cognition, were selectively upregulated only in the OVX hCG-treated group. RNA sequencing analyses identified a significant increase in peripheral myeloid and pro-inflammatory genes within the hippocampi of the OVX group that were completely reversed by hCG, identifying a potential mechanism underlying the selective therapeutic effect of LHCGR activation. Interestingly, in intact mice, hCG administration mimicked the effects of gonadectomy. Together, our findings indicate that CNS LHCGR agonism in the ...
Source: Biochimica et Biophysica Acta - Category: Biochemistry Authors: Source Type: research