Bile Acids in Neurodegenerative Disorders

Abstract

Bile acids, a structurally related group of molecules derived from cholesterol, have a long history as therapeutic agents in medicine, from treatment for primarily ocular diseases in ancient Chinese medicine to modern day use as approved drugs for certain liver diseases. Despite evidence supporting a neuroprotective role in a diverse spectrum of age-related neurodegenerative disorders, including several small pilot clinical trials, little is known about their molecular mechanisms or their physiological roles in the nervous system. We review the data reported for their use as treatments for neurodegenerative diseases and their underlying molecular basis. While data from cellular and animal models and clinical trials support potential efficacy to treat a variety of neurodegenerative disorders, the relevant bile acids, their origin, and the precise molecular mechanism(s) by which they confer neuroprotection are not known delaying translation to the clinical setting.

TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti‐Inflammatory Effects in Microglial Cells

“…The concentration of TUDCA used in the present study was selected on the basis of previous reports (Keene et al, ; Rodrigues et al, , ; for review see Ackerman and Gerhard, ) and according to our previous work (Yanguas‐Casás et al, , ).…”

The association between HSD3B7 gene variant and Parkinson's disease in ethnic Chinese

“…No statistical heterogeneity was found among 12 included studies undergoing the same UKPDBB criteria ( I 2  = 31). Notably, the result also revealed that allele A was less frequent in PD than in controls ( p  =   5.81 × 10 −6 , OR = 0.90, 95% CI: 0.88–0.94, Figure S1), suggesting HSD3B7 , in a protective manner, is a potential candidate locus for PD (Ackerman & Gerhard, 2016). …”

“…Considering the neuroprotective effects of bile acids, a set of neurodegenerative diseases have been reported, including PD, Alzheimer's disease (AD), and Huntington's disease (HD), but the available data for HSD3B7 are limited (Ackerman & Gerhard, 2016; Ramalho et al., 2013; Rodrigues et al., 2000). Astrocyte expressing HSD3B7 is responsible for degradation of oxysterol, the active oxidized product of cholesterol, which can be used as a marker of brain atrophy in patients holding aging neurons with AD and HD (Leoni & Caccia, 2011; Rutkowska, Preuss, Gessier, Sailer, & Dev, 2015).…”

“…In the classical pathway, HSD3B7 catalyzes the second step of bile acid formation (Monte, Marin, Antelo, & Vazquez‐Tato, 2009), and its mutations may reduce the synthetic capability (Cheng et al., 2003). Interestingly, when the main product, chenodeoxycholic acid (CDCA), converts into a β‐configuration ursodeoxycholic acid (UDCA) and its taurine‐conjugated form (TUDCA), the anti‐apoptotic effect is demonstrated (Ackerman & Gerhard, 2016; Amaral, Viana, Ramalho, Steer, & Rodrigues, 2009; Hirano, Masuda, & Oda, 1981). In a PD module, UDCA significantly attenuated programed cell death events and protected human dopaminergic SH‐SY5Y cells through the PI3K‐Akt/PKB signaling pathways, similarly, UDCA deregulated the level of rotenone‐induced apoptosis by modulating mitochondrial dysfunction (Abdelkader, Safar, & Salem, 2016; Chun & Low, 2012).…”

“…However, current work to discover the physiological roles of bile acids in neurodegenerative conditions mostly focused on UDCA and TUDCA, little has been performed on the initial stage that HSD3B7 gene is involved (Ackerman & Gerhard, 2016). Given the limited power to identify disease gene by GWAS or pathway‐based approaches and the neuroprotective potential of bile acids for PD, replication studies are needed from different ethnic groups (Wang, Li, & Hakonarson, 2010).…”