Tau clearance improves astrocytic function and brain glutamate-glutamine cycle

Hebron, Michaeline; Javidnia, Monica; Moussa, Charbel

doi:10.1016/j.jns.2018.06.005

Cited by 41 publications

(47 citation statements)

References 63 publications

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“…In the present study, there were increased glutamine/glutamate ratios in 12–14-month-old PS19 mice in the 5 out of 6 brain regions examined, indicating that tau accumulation significantly affects the glutamate–glutamine relationship in the brain with age. Herbron et al (2018) produced TauP301L mice with a widespread tau accumulation in the brain by crossbreeding male and female hemizygous rTg4510 mice under the control of prion protein promotor. Interestingly, 13 C/ 1 H magnetic resonance spectroscopy revealed that TauP301L mice at 2–3 months of age displayed increased glutamate and GABA levels, but decreased glutamine levels, in the brainstem and striatal extracts when compared to the other genotype groups.…”

Section: Discussionmentioning

confidence: 99%

Altered brain arginine metabolism in a mouse model of tauopathy

Vemula

Zhang

et al. 2019

Amino Acids

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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.

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Section: Discussionmentioning

confidence: 99%

Altered brain arginine metabolism in a mouse model of tauopathy

Vemula

Zhang

et al. 2019

Amino Acids

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“…[7][8][9][10][11] One study demonstrated that a reduction of tau in nilotinib-treated models of tauopathies results in enhanced astrocyte activity and improved neurotransmitter balance. 25 Autophagy clearance of α-synuclein and tau is concurrent with improved astrocytic activity and balance of neurotransmitters, including dopamine. 9,10,[25][26][27] Collectively, the effects of nilotinib on CSF biomarkers indicate that a reduction of oligomeric α-synuclein and p-tau may improve dopamine metabolism in patients with PD.…”

Section: Research Original Investigationmentioning

confidence: 99%

“…25 Autophagy clearance of α-synuclein and tau is concurrent with improved astrocytic activity and balance of neurotransmitters, including dopamine. 9,10,[25][26][27] Collectively, the effects of nilotinib on CSF biomarkers indicate that a reduction of oligomeric α-synuclein and p-tau may improve dopamine metabolism in patients with PD. Nilotinib preferentially targets Abl 4-6 and discoidin domain receptors.…”

Section: Research Original Investigationmentioning

confidence: 99%

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease

et al. 2020

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IMPORTANCE This study evaluated nilotinib safety and its effects on biomarkers as a potential disease-modifying drug in Parkinson disease.OBJECTIVES To assess nilotinib effects on safety and pharmacokinetics and measure the change in exploratory biomarkers in patients with moderately severe Parkinson disease. DESIGN, SETTING, AND PARTICIPANTSThis was a single-center, phase 2, randomized, double-blind, placebo-controlled trial with 300 patients approached in clinic; of these, 200 declined to participate, 100 were screened, 25 were excluded, and 75 were randomized 1:1:1 into placebo; nilotinib, 150-mg; or nilotinib, 300-mg groups. Recruitment started on May 17, 2017, and ended April 28, 2018, and follow-up ended August 10, 2019. Parkinson disease was confirmed according to the UK Brain Bank diagnostic criteria and symptoms were stabilized with use of optimal levodopa and/or dopamine agonists and other medications used in Parkinson disease.INTERVENTIONS Nilotinib vs placebo, administered orally once daily for 12 months followed by a 3-month washout period.MAIN OUTCOMES AND MEASURES It was hypothesized that nilotinib is safe and can be detected in the cerebrospinal fluid, where it alters exploratory biomarkers via inhibition of Abelson tyrosine kinase and potentially improves clinical outcomes. RESULTSOf the 75 patients included in the study, 55 were men (73.3%); mean (SD) age was 68.4 (8.2) years. Doses of 150 or 300 mg of nilotinib were reasonably safe, although more serious adverse events were detected in the nilotinib (150 mg: 6 [24%]; 300 mg: 12 [48%]) vs placebo (4 [16%]) groups. The 150-mg nilotinib group showed an increase in cerebrospinal fluid levels of the dopamine metabolites homovanillic acid (159.80nM; 90% CI, 7.04-312.60nM; P = .04) and 3,4-dihydroxyphenylacetic acid (4.87nM; 90% CI, 1.51-8.23nM; P = .01), and the 300-mg nilotinib group showed an increase in 3,4-dihydroxyphenylacetic acid (7.52nM; 90% CI, 2.35-12.69nM; P = .01). The nilotinib 150-mg but not the nilotinib 300-mg group demonstrated a reduction of α-synuclein oligomers (−0.04 pg/mL; 90% CI, −0.08 to 0.01 pg/mL; P = .03). A significant reduction of hyperphosphorylated tau levels was seen in the nilotinib 150-mg (−10.04 pg/mL; 90% CI, −17.41 to −2.67 pg/mL; P = .01) and nilotinib 300-mg (−12.05 pg/mL; 90% CI, −19.21 to −4.90 pg/mL; P = .01) groups.CONCLUSIONS AND RELEVANCE In this study, nilotinib appeared to be reasonably safe and detectable in the cerebrospinal fluid. Exploratory biomarkers were altered in response to nilotinib. Taken together, these data will guide the development of a phase 3 study to investigate the effects of nilotinib therapy in patients with Parkinson disease. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02954978

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“…3 Nilotinib (Tasigna, AMN107; Novartis, Switzerland) is a tyrosine kinase inhibitor that preferentially targets discoidin domain receptors (DDRs) [4][5][6][7][8] and effectively reduces misfolded proteins in animal models of neurodegeneration. 7,[9][10][11][12][13][14][15][16] Nilotinib also targets the nonreceptor tyrosine kinase Abelson [4][5][6] and is FDAapproved for the treatment of Philadelphia chromosome positive chronic myeloid leukemia (CML) at oral doses of 300 mg twice daily. [4][5][6] Low doses of nilotinib penetrate the bloodbrain barrier and promote the degradation of Aβ and tau in animal models of neurodegeneration.…”

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confidence: 99%

“…[4][5][6] Low doses of nilotinib penetrate the bloodbrain barrier and promote the degradation of Aβ and tau in animal models of neurodegeneration. 7,[9][10][11][12][13][14][15][16] Clinical studies indicate that nilotinib enters the central nervous system (CNS; peak plasma concentration [C max ] 2-4 nM in cerebrospinal fluid [CSF]), increases dopamine turnover, and reduces CSF tau, independent of Abelson inhibition [17][18][19] -further suggesting that nilotinib effects may be mediated by DDR1 inhibition (half-maximal inhibitory concentration [IC 50 ] 1-8 nM). 8,20,21 The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of nilotinib in participants with mild to moderate dementia due to AD.…”

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confidence: 99%

Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

Turner

Hebron

Lawler

et al. 2020

Annals of Neurology

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Objective Preclinical evidence with nilotinib, a US Food and Drug Administration (FDA)‐approved drug for leukemia, indicates improvement in Alzheimer's disease phenotypes. We investigated whether nilotinib is safe, and detectable in cerebrospinal fluid, and alters biomarkers and clinical decline in Alzheimer's disease. Methods This single‐center, phase 2, randomized, double‐blind, placebo‐controlled study investigated the safety, tolerability, and pharmacokinetics of nilotinib, and measured biomarkers in participants with mild to moderate dementia due to Alzheimer's disease. The diagnosis was supported by cerebrospinal fluid or amyloid positron emission tomography biomarkers. Nilotinib 150 mg versus matching placebo was taken orally once daily for 26 weeks followed by nilotinib 300 mg versus placebo for another 26 weeks. Results Of the 37 individuals enrolled, 27 were women and the mean (SD) age was 70.7 (6.48) years. Nilotinib was well‐tolerated, although more adverse events, particularly mood swings, were noted with the 300 mg dose. In the nilotinib group, central nervous system (CNS) amyloid burden was significantly reduced in the frontal lobe compared to the placebo group. Cerebrospinal fluid Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months in the nilotinib group compared to the placebo. Hippocampal volume loss was attenuated (−27%) at 12 months and phospho‐tau‐181 was reduced at 6 months and 12 months in the nilotinib group. Interpretation Nilotinib is safe and achieves pharmacologically relevant cerebrospinal fluid concentrations. Biomarkers of disease were altered in response to nilotinib treatment. These data support a larger, longer, multicenter study to determine the safety and efficacy of nilotinib in Alzheimer's disease. ANN NEUROL 2020 ANN NEUROL 2020;88:183–194

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Tau clearance improves astrocytic function and brain glutamate-glutamine cycle

Cited by 41 publications

References 63 publications

Altered brain arginine metabolism in a mouse model of tauopathy

Altered brain arginine metabolism in a mouse model of tauopathy

Nilotinib Effects on Safety, Tolerability, and Potential Biomarkers in Parkinson Disease

Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer's Disease

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