TUDCA, a Bile Acid, Attenuates Amyloid Precursor Protein Processing and Amyloid-β Deposition in APP/PS1 Mice

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid-β (Aβ) peptide in the hippocampus and frontal cortex of the brain, leading to progressive cognitive decline. The endogenous bile acid tauroursodeoxycholic acid (TUDCA) is a strong neuroprotective agent in several experimental models of disease, including neuronal exposure to Aβ. Nevertheless, the therapeutic role of TUDCA in AD pathology has not yet been ascertained. Here we report that feeding APP/PS1 double-transgenic mice with diet containing 0.4 % TUDCA for 6 months reduced accumulation of Aβ deposits in the brain, markedly ameliorating memory deficits. This was accompanied by reduced glial activation and neuronal integrity loss in TUDCA-fed APP/PS1 mice compared to untreated APP/PS1 mice. Furthermore, TUDCA regulated lipid-metabolism mediators involved in Aβ production and accumulation in the brains of transgenic mice. Overall amyloidogenic APP processing was reduced with TUDCA treatment, in association with, but not limited to, modulation of γ-secretase activity. Consequently, a significant decrease in Aβ(1-40) and Aβ(1-42) levels was observed in both hippocampus and frontal cortex of TUDCA-treated APP/PS1 mice, suggesting that chronic feeding of TUDCA interferes with Aβ production, possibly through the regulation of lipid-metabolism mediators associated with APP processing. These results highlight TUDCA as a potential therapeutic strategy for the prevention and treatment of AD.

Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

“…The bile acids TUDCA and UDCA have protective effects in several protein folding neurodegenerative disease models, including AD, HD, and PD (10)(11)(12). In the present study, we tested the efficacy of these compounds in prion disease, both in terms of their effect on prion protein aggregation and their ability to prevent neuronal loss induced by prion infection.…”

“…APP/PS1 transgenic mice (an AD model) fed TUDCA had fewer deposits of pathological protein and fewer memory deficits (10). TUDCA treatment of HD transgenic mice led to reduced neuropathology and an improved clinical phenotype (11).…”

Inherent Instability of the Retinitis Pigmentosa P23H Mutant Opsin

“…Frederick et al (60) then generated a P23H TG mouse on a rhodopsin knock-out background, and they reported that GHL (P23H)/ Rho Ϫ/Ϫ mice failed to form ROS and that P23H rhodopsin mainly accumulated in the outer nuclear layer. P23H TG rat line-3 is the most commonly used animal model for gene therapy and drug testing (12,21,22,(77)(78)(79)(80)(81)(82)(83), but immunochemistry showed rhodopsin is localized in the ROS of this TG rat (84). The P23H transgene has also been expressed in Xenopus, revealing an inner segment accumulation (10).…”

Bile Acids in Neurodegenerative Disorders

“…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).…”