Evaluating the efficacy of purchased antisense oligonucleotides to reduce mouse and human tau in vivo.

Many preclinical and clinical studies support the use of antisense oligonucleotides (ASOs) as effective therapeutic strategies. However, acquiring ASOs for research purposes may be limited by partnerships with the pharmaceutical companies. Our lab previously developed an effective ASO strategy to lower human tau and reverse pathology in aged tauopathy model mice. Testing the efficacy of purchased tau lowering ASOs would provide support for these reagents as broad research tools. Purchased mouse and human tau lowering ASOs were infused or injected intracerebroventricularly into wildtype and tau transgenic mice. Following treatment, brain tissue evaluated for ASO distribution and levels of tau mRNA, protein, and phosphorylated tau. We show that purchased ASOs enter cell types of the brain and effectively decrease mouse or human tau mRNA and protein levels. Human tau lowering ASO treatment in PS19 mice decreased phosphorylated tau and gliosis relative to saline-treated PS19 mice, consistent with our previous study using a non-commercial tau lowering ASO. The results of this study demonstrate the efficacy of purchased tau targeting ASOs in vivo to support their broad use by researchers.

Altered brain arginine metabolism with age in the APPswe/PSEN1dE9 mouse model of Alzheimer's disease.

Amyloid-beta (Aß) cleaved from amyloid precursor protein (APP) has been proposed to play a central and causative role in the aetiology of Alzheimer's disease (AD). APPswe/PSEN1dE9 (APP/PS1) transgenic mice display chronic Aß accumulation and deposition in the brain. L-arginine is a semi-essential amino acid with a number of bioactive metabolites, and altered arginine metabolism has been implicated in the pathogenesis and/or the development of AD. This study systematically investigated how arginine metabolic profiles changed in the frontal cortex, hippocampus, parahippocampal region and cerebellum of male APP/PS1 mice at 4, 9 and 17 months of age relative to their sex- and age-matched wildtype controls. Immunohistochemistry demonstrated age-related Aß deposition in the brain. High-performance liquid chromatography and mass spectrometry revealed age-related increases in glutamine, spermidine and spermine in APP/PS1 mice in a region-specific manner. Notably, genotype-related increases in spermine were found in the frontal cortex at the 9-month age point and in the frontal cortex, hippocampus and parahippocampal region at 17 months of age. Given the existing literature indicating the role of polyamines (spermine in particular) in modulating the aggregation and toxicity of Aß oligomers, increased spermidine and spermine levels in APP/PS1 mice may be a neuroprotective mechanism to combat Aß toxicity. Future research is required to better understand the functional significance of these changes.

Altered brain arginine metabolism in a mouse model of tauopathy.

Tauopathies consist of intracellular accumulation of hyperphosphorylated and aggregated microtubule protein tau, which remains a histopathological feature of Alzheimer's disease (AD) and frontotemporal dementia. L-Arginine is a semi-essential amino acid with a number of bioactive molecules. Its downstream metabolites putrescine, spermidine, and spermine (polyamines) are critically involved in microtubule assembly and stabilization. Recent evidence implicates altered arginine metabolism in the pathogenesis of AD. Using high-performance liquid chromatographic and mass spectrometric assays, the present study systematically determined the tissue concentrations of L-arginine and its nine downstream metabolites in the frontal cortex, hippocampus, parahippocampal region, striatum, thalamus, and cerebellum in male PS19 mice-bearing human tau P301S mutation at 4, 8, and 12-14 months of age. As compared to their wild-type littermates, PS19 mice displayed early and/or prolonged increases in L-ornithine and altered polyamine levels with age. There were also genotype- and age-related changes in L-arginine, L-citrulline, glutamine, glutamate, and γ-aminobutyric acid in a region- and/or chemical-specific manner. The results demonstrate altered brain arginine metabolism in PS19 mice with the most striking changes in L-ornithine, polyamines, and glutamate, indicating a shift of L-arginine metabolism to favor the arginase-polyamine pathway. Given the role of polyamines in maintaining microtubule stability, the functional significance of these changes remains to be explored in future research.