Background Bile acids are a structurally related group of molecules derived from cholesterol that are widely known for their role as chemical detergents involved in the intestinal absorption and transport of fats and lipid-soluble nutrients (Schonewille et al., 2016). However, bile acids also appear to play as yet poorly defined physiological roles in the central nervous system (Lieu et al., 2014). Surprisingly little work has been done on the physiological roles of bile acids in neurons or the central nervous system (Zhang et al., 1997) despite a wide array of data in model systems and despite the significant therapeutic advantages of bile acids. Bile acids are readily bioavailable via oral, subcutaneous, or intravenous administration, can cross the blood-brain barrier, are relatively nontoxic, and have been approved by the U.S. Food and Drug Administration for human therapeutic use. We review evidence supporting a potentially therapeutic role for bile acids in a number of diverse neurodegenerative conditions. A summary of the studies described below is presented in Tables 1, 2. Table 1 Model system and human data implicating bile acids in neurodegenerative disorders. Disease/Phenotype Model Bile acid Mode of administration Dose or concentration Effects References Spinocerebellar ataxia type 1 (SCA1) Transgenic mouse with human ATXN1 with 82 CAG trinucleotide repeats under control of a Purkinje-cell promoter TUDCA Subcutaneous injection 500 mg/kg TUDCA crossed the blood-brain barrier but had no effect on cell survival Kaemmerer et al., 2001 Huntington's disease (HD) 3-nitropropionic acid-treated rat neuronal RN33B cells TUDCA Media 100 μM Decreased apoptosis by preventing mitochondrial depolarization and outer membrane disruption Rodrigues et al., 2000 GUDCA 500 μM UDCA 500 μM HD 3-nitropropionic acid-treated rats TUDCA Intraperitoneal injection 50 mg/kg Decreased apoptosis Keene et al., 2001 Reduced lesion volume Preserved sensorimotor and cognitive function HD R6/2 transgenic mouse with 150 CAG trinucleotide repeats in exon 1 of the huntingtin gene TUDCA Subcutaneous injection 500 mg/kg Reduced striatal cell apoptosis Keene et al., 2002 Decreased levels of intracellular inclusions Improved locomotor and sensorimotor function Parkinson's disease (PD) Sodium nitroprusside-treated human dopaminergic SH-SY5Y cells UDCA Media 50–200 μM Dose dependent inhibition of apoptosis via the PI3K- Chun and Low, 2012 Akt/PKB pathways Reduced ROS and reactive nitrogen species Maintained intracellular GSH levels PD Skin fibroblasts from PD patients UDCA Media 10–100 nM Restored mitochondrial function dependent upon glucocorticoid receptor activation and Akt phosphorylation Mortiboys et al., 2013 PD MPTP-induced mouse model TUDCA Intraperitoneal injection 50 mg/kg Reduction in loss of dopaminergic neurons by preserving levels of phosphorylated JNK, reducing ROS levels, and activating the Akt pathway Castro-Caldas et al., 2012 Alzheimer's disease (AD) Aβ-treated primary rat cortical neurons TUDCA Media 100 μM Decreased nuclear fragmentation and cytochrome c release through the PI3K pathway Solá et al., 2003 AD Aβ-treated mouse BV-2 microglial cells UDCA Media 250 μM Anti-inflammatory effect by inhibiting NF-κB activation Joo et al., 2004 AD Aβ-treated primary rat cortical neurons UDCA TUDCA Media 100 μM Decreased apoptosis dependent on interaction with the mineralocorticoid receptor Sola et al., 2006 AD Double transgenic APP/PS1 mice TUDCA Diet 0.4% wt/wt Reduced amyloid plaque number Nunes et al., 2012; Ramalho et al., 2013 Decreased injury to neurons Improved memory retention Decreased the loss of a postsynaptic marker in the hippocampus Amyotrophic lateral sclerosis (ALS) Mouse NSC-34 cells with the human SOD1G93A mutation GUDCA Media 50 μM Decreased cell death by blocking caspase-9 activation Vaz et al., 2015 ALS Primary mouse ventral midbrain cultures CA Media 10 μM Increased neuronal survival and promoted neurogenesis via LXR Theofilopoulos et al., 2013 ALS Clinical trial with ALS patients UDCA Oral Up to 50 mg/kg UDCA is well tolerated and well absorbed by oral administration Parry et al., 2010 UDCA crosses the blood-brain barrier in a dose-dependent manner ALS Clinical trial with ALS patients UDCA Oral 3.5 g/140 mL/day Slight decrease in progression of ALS but results were inconclusive Min et al., 2012 ALS Clinical trial with ALS patients TUDCA Oral 1 g, twice daily TUDCA is well tolerated Elia et al., 2016 Treatment resulted in improved function and slowed disease progression Prion disease Prion infected male mice UDCA Diet 0.01% wt/wt Reduced astrogliosis Cortez et al., 2015 Prolonged survival Cerebrotendinous xanthomatosis (CTX) Human patients CDCA Oral 15 mg/kg/day Amelioration of neurological symptoms Bjorkhem, 2013 Improved prognosis Retinitis pigmentosa (RP) Homozygous P23H rhodopsin transgenic rats TUDCA Intraperitoneal injection 500 mg/kg Reduced photoreceptor loss Fernandez-Sanchez et al., 2011 Preserved structure, function, and synaptic contacts of rods and cones RP Transgenic rd10 mouse model TUDCA Subcutaneous injection 500 mg/kg Higher cone cell density from decreased apoptosis Preserved structure and function of photoreceptor cells Boatright et al., 2006; Phillips et al., 2008; Oveson et al., 2011 Light-induced retinal degeneration Light-induced retinal damage (LIRD) mouse model TUDCA Subcutaneous injection 500 mg/kg Higher cone cell density from decreased apoptosis Preserved structure and function of photoreceptor cells Boatright et al., 2006; Phillips et al., 2008; Oveson et al., 2011 Leber congenital amaurosis Homozygous LRAT knockout mice TUDCA Subcutaneous injection 500 mg/kg Slowed cone degeneration in the ventral and central retina by preventing apoptosis and increasing ER-associated protein degradation Zhang et al., 2012; Fu and Zhang, 2014 In vitro retinal degeneration Whole mount cat retinas TUDCA Media 0.5 μM Greater receptive field size Xia et al., 2015 Decreased irradiance threshold Maintenance of the contrast threshold Retinal dystrophy Primary human retinal epithelium cells TUDCA Media 100 μM Protective against H2O2-induced impairment of phagocytosis Murase et al., 2015 Retinal detachment Subretinal injection of hyaluronic acid in rats TUDCA Intraperitoneal injection 500 mg/kg Reduced apoptosis in the outer nuclear layer of the retina Mantopoulos et al., 2011 Decreased caspase activation and protein carbonyl production Diabetic retinopathy Primary rat retinal neuron cells exposed to elevated glucose TUDCA Media 100 μM Decreased apoptosis Gaspar et al., 2013 Decreased mito-nuclear translocation of apoptosis-inducing factor (AIF) Decreased ROS and protein carbonyl production Retinal ganglion cell degeneration Intravitreal injection of NMDA in rats TUDCA Intraperitoneal injection 500 mg/kg Increased survival of retinal ganglion cells Gomez-Vicente et al., 2015 Ischemic stroke Middle cerebral artery occlusion in rats TUDCA Intravenous injection 400 mg/kg Reduction in infarct size Rodrigues et al., 2002 Reduced apoptosis Preserved mitochondrial integrity Hemorrhagic stroke Collagenase TUDCA Intra-arterial injection 200 mg/kg Decreased lesion volumes, peri-hematoma apoptosis, caspase activity, NF-κB activiation; increased AKT activation, neurobehavioral improvement Rodrigues et al., 2003 Acute neuroinflammation Intracerebro-ventricular injection with LPS in mice TUDCA Intraperitoneal injection 500 mg/kg Reduced glial cell activation Yanguas-Casás et al., 2014 Acute neuroinflammation Primary cultures of microglial cells and astrocytes from rats treated with LPS and/or IFN-γ TUDCA Media 200 μM Reduced microglial chemotaxis and expression of MCP-1 and VCAM-1 Yanguas-Casás et al., 2014 Sleep-wake pattern Wild type and histamine deficient mice UDCA Diet 32 mg/kg Promotes wakefulness through disinhibition of the histaminergic system via GABAA receptors Yanovsky et al., 2012 Hypothalamic network activity Primary cultures of mouse posterior hypothalamus CA Media Up to 8 mM Reduced firing, synchronized network activity, and blocked GABAA and NMDA receptor activity Schubring et al., 2012 GCA TCA DCA TDCA CDCA GCDCA TCDCA DHCA Neurotransmitter release Sympathetic ganglion neurons isolated from of adult bull frogs CA Media 1 μM Inhibits N-type calcium channel currents Lee et al., 2012 Hyperbilirubinemia Unconjugated bilirubin-treated organotypic-cultured hippocampal slices from rats GUDCA Media 50 mM Decreased cell death, NOS, glutamate release Silva et al., 2012 Glutamate-induced neurotoxicity Glutamate-treated primary rat cortical neurons TUDCA Media 100 μM Decreased apoptosis by activating a PI3K-dependent Bad signaling pathway Castro et al., 2004 Table 2 Genomic and metabolomics data implicating bile acids in neurodegenerative disorders. Disease Approach Genetic association References PD Meta-analysis of GWAS data from PD and normal patients HSD3B7 missense SNP in HSD3B7, Cheng et al., 2003; Song and Lee, 2013 PD Meta-analysis of PD miRNA GWAS data SNPs in a miRNA-binding site in the 3' UTR of HSD3B7 Ghanbari et al., 2016 ALS Peripheral blood cell eQTL of ALS and normal patients CYP27A1 eQTL Diekstra et al., 2012 AD Plasma metabolomic analysis of AD and normal patients Increased plasma GUDCA levels in patients with mild cognitive impairment or AD Mapstone et al., 2014