Cholestasis-Induced Cognitive Decline: Neurological Mechanisms and Therapeutic Implications

Abstract

Ph. D. ThesisCognitive dysfunction occurs during the cholestatic liver disease Primary biliary Cholangitis (PBC). Patients experience with short-term memory and concentration deficit, termed ‘brain fog’. This can be debilitating and severely affect quality of life, with no beneficial treatments (Newton, Hollingsworth et al. 2008) In this thesis, using the murine Bile Duct Ligation (BDL) model and in vitro modelling with human neuronal cells, I investigated the effects of cholestasis on the blood-brain barrier (BBB) and resultant changes within the brain. This study focussed on the hippocampus due to its crucial role in learning and memory. Changes to BBB could be observed from day 6, including astrocyte detachment, and permeability using MRI. By day 10 mice had visual spatial memory deficits, neuroinflammation was seen within the hippocampus, and changes were observed in gamma frequency oscillations. Interestingly, neurons in the hippocampus possessed features of senescence in cholestatic mice (telomere associated DNA damage, and P21+ RNA), highlighting parallels in pathology between the liver (where senescence is known to occur during cholestasis) and the brain. This effect was mirrored during in vitro studies, where neurons treated with PBC patient serum (to simulate pathological exposure to bile acids) also displayed increased sen-B-gal, a feature of senescence. In another strand, I examined the ability of both approved (ursodeoxycholic acid, Obeticholic Acid) and experimental (Bezafibrate) therapies to modify cognitive processes. Only Obeticholic Acid provides a potential therapeutic due to its in vivo and in vitro effects. Strikingly, OCA improve cognition and reduces neuronal senescence in BDL mice and in vitro when neurons are pre-treated before serum treatments. Therefore, the data presented in this thesis implicates senescence as a key pathological feature of cholestatic disease not just in the liver but also in brain where it has been previously linked to poor cognition (Baker, Wijshake et al. 2011, Fielder, Tweedy et al. 2020). Further investigation of early intervention with OCA may prove beneficial to patients experiencing cognitive deficit