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Acidified drinking water attenuates motor deficits and brain pathology in a mouse model of a childhood neurodegenerative disorder.

ABSTRACT: We recently demonstrated that HCl-acidified drinking water, which is widely used in laboratory animal facilities, had some beneficial effects in the Cln3^-/- mouse model of juvenile Batten disease, a neurodegenerative lysosomal storage disorder¹. Here we tested if acidified drinking water has therapeutic effects in Cln1^R151X nonsense mutant mice, a model of the infantile form of Batten disease. In Cln1^R151X mice, acidified drinking water received from weaning prevented the impairment in pole climbing ability measured at 3 and 6 months of age. Histopathological analysis of the brain at 6 months showed that acidified drinking water decreased the amount of lysosomal storage material, reduced astrocytosis in the striatum and somatosensory barrelfield cortex, and attenuated microglial activation in the thalamus. Compared to wild-type mice, the gut microbiota of Cln1^R151X mice was markedly different. Acidified drinking water significantly altered the gut microbiota composition of Cln1^R151X mice, indicating a contribution of gut bacteria to the therapeutic effects of acidified water. Our results in Cln1^R151X mice suggest that acidified drinking water may have beneficial effects for patients with infantile Batten disease. This study also verifies that acidified drinking water can modify disease phenotypes in mouse models, contributing to the inter-laboratory variations in neurological and pathological findings.

SUBMITTER: Kovacs AD

PROVIDER: S-EPMC9151921 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Acidified drinking water attenuates motor deficits and brain pathology in a mouse model of a childhood neurodegenerative disorder.

Kovács Attila D AD Langin Logan M LM Hernandez Jose L Gonzalez JLG Pearce David A DA

Scientific reports 20220530 1

We recently demonstrated that HCl-acidified drinking water, which is widely used in laboratory animal facilities, had some beneficial effects in the Cln3-/- mouse model of juvenile Batten disease, a neurodegenerative lysosomal storage disorder1. Here we tested if acidified drinking water has therapeutic effects in Cln1R151X nonsense mutant mice, a model of the infantile form of Batten disease. In Cln1R151X mice, acidified drinking water received from w ...[more]

PMID: 35637265

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Project description:BackgroundAlzheimer's disease (AD), affecting many elders worldwide, is characterized by A-beta and tau-related cognitive decline. Accumulating evidence suggests that brain iron accumulation is an important characteristic of AD. However, the function and mechanism of the iron-mediated gut-brain axis on AD is still unclear.MethodsA Caenorhabditis elegans model with tau-overexpression and a high-Fe diet mouse model of cognitive impairment was used for probiotic function evaluation. With the use of qPCR, and immunoblotting, the probiotic regulated differential expression of AD markers and iron related transporting genes was determined. Colorimetric kits, IHC staining, and immunofluorescence have been performed to explore the probiotic mechanism on the development of gut-brain links and brain iron accumulation.ResultsIn the present study, a high-Fe diet mouse model was used for evaluation in which cognitive impairment, higher A-beta, tau and phosphorylated (p)-tau expression, and dysfunctional phosphate distribution were observed. Considering the close crosstalk between intestine and brain, probiotics were then employed to delay the process of cognitive impairment in the HFe mouse model. Pediococcus acidilactici (PA), but not Bacillus subtilis (BN) administration in HFe-fed mice reduced brain iron accumulation, enhanced global alkaline phosphatase (AP) activity, accelerated dephosphorylation, lowered phosphate levels and increased brain urate production. In addition, because PA regulated cognitive behavior in HFe fed mice, we used the transgenic Caenorhabditis elegans with over-expressed human p-tau for model, and then PA fed worms became more active and longer lived than E.coli fed worms, as well as p-tau was down-regulated. These results suggest that brain iron accumulation influences AD risk proteins and various metabolites. Furthermore, PA was shown to reverse tau-induced pathogenesis via iron transporters and AP-urate interaction.ConclusionsPA administration studies demonstrate that PA is an important mediator of tau protein reduction, p-tau expression and neurodegenerative behavior both in Caenorhabditis elegans and iron-overload mice. Finally, our results provide candidates for AP modulation strategies as preventive tools for promoting brain health. Video Abstract.

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Acidified drinking water attenuates motor deficits and brain pathology in a mouse model of a childhood neurodegenerative disorder.

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Acidified drinking water attenuates motor deficits and brain pathology in a mouse model of a childhood neurodegenerative disorder.

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