Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice

Lo, Adrian C.; Callaerts-Végh, Zsuzsanna; Nunes, Ana V. M.; Rodrigues, Cecília M. P.; D’Hooge, Rudi

doi:10.1016/j.nbd.2012.09.003

Cited by 99 publications

(83 citation statements)

References 61 publications

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“…To further evaluate the role of ER stress in poly(GA)-induced toxicity, neurons expressing GFP-(GA) 50 were treated with the chemical chaperone TUDCA, an inhibitor of ER stress and associated toxicity [13, 38, 52, 72]. Compared to vehicle-treated neurons expressing GFP-(GA) 50 , those treated with TUDCA (0.25 and 0.5 mM) showed a significant decrease in LDH activity in media (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with these findings, we show that salubrinal, a selective inhibitor of the GADD34–PP1C complex [9, 36, 60], restored eIF2α phosphorylation, reduced ER stress and increased cell survival in neurons expressing poly(GA) proteins. In addition, TUDCA, an inhibitor of ER stress [13, 38, 52, 72], blocked the increase in phospho-PERK and CHOP normally observed in poly(GA)-expressing neurons, and provided neuroprotection against poly(GA)-induced toxicity. Of interest, the levels of poly(GA) and ubiquitinated proteins were not themselves decreased after salubrinal and TUDCA treatment, suggesting that proteasome inhibition, the culprit responsible for inducing ER stress, remained present in these cells.…”

Section: Discussionmentioning

confidence: 99%

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Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

et al. 2014

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The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1336-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

et al. 2014

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“…In double transgenic mice (APP/PS1) that express human amyloid precursor protein carrying the KM670/671NL Swedish double mutation and the human presenilin 1 L166P mutation under the regulation of a neuron-specific promoter, treatment via dietary supplementation of standard laboratory chow with 0.4% (wt/wt) of TUDCA significantly reduced amyloid plaque number in the frontal cortex and hippocampus, decreased injury to neurons measured by determining loss of, or damage to, neuronal fibers surrounding plaques, and improved memory retention measured via contextual, though not auditory, fear conditioning (Nunes et al, 2012) as well as reduced hippocampal and prefrontal amyloid deposition (Lo et al, 2013). TUDCA has also been shown to help preserve the postsynaptic marker postsynaptic density-95 in the hippocampus of APP/PS1 mice (Ramalho et al, 2013).…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Bile Acids in Neurodegenerative Disorders

Ackerman

Gerhard

2016

Front. Aging Neurosci.

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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.

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“…The same trend was observed for cholesterol sulfate, a component of cell membranes where it plays a stabilizing role [57], not previously described to our knowledge in AD research. Finally, reductions of brain deoxycholic and taurocholic acids (or isomers) could be behind different neuropathological conditions, given that ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) have been demonstrated to be potent inhibitors of apoptosis [58], and they present neuroprotective action against amyloid deposition [59]. Other potential markers found by metabolomic fingerprinting of brain tissues could be related to failures in neurotransmitter systems, including deficits in tyrosine, dopamine and aspartate, as well as increased N1-acetylspermidine (Table 4).…”

Section: Metabolitementioning

confidence: 99%

Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry

González‐Domínguez

García-Barrera

Vitórica

et al. 2015

Journal of Pharmaceutical and Biomedical Analysis

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The identification of pathological mechanisms underlying to Alzheimer's disease is of great importance for the discovery of potential markers for diagnosis and disease monitoring. In this study, we investigated regional metabolic alterations in brain from the APP/PS1 mice, a transgenic model that reproduces well some of the neuropathological and cognitive deficits observed in human Alzheimer's disease. For this purpose, hippocampus, cortex, cerebellum and olfactory bulbs were analyzed using a high-throughput metabolomic approach based on direct infusion mass spectrometry. Metabolic fingerprints showed significant differences between transgenic and wild-type mice in all brain tissues, being hippocampus and cortex the most affected regions. Alterations in numerous metabolites were detected including phospholipids, fatty acids, purine and pyrimidine metabolites, acylcarnitines, sterols and amino acids, among others. Furthermore, metabolic pathway analysis revealed important alterations in homeostasis of lipids, energy management, and metabolism of amino acids and nucleotides. Therefore, these findings demonstrate the potential of metabolomic screening and the use of transgenic models for understanding pathogenesis of Alzheimer's disease.

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Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice

Cited by 99 publications

References 61 publications

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

Bile Acids in Neurodegenerative Disorders

Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry

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