The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer’s Disease

Sorgdrager, Freek J. H.; Ley, CP van Der; Faassen, Martijn van; Calus, Elke; Nollen, E. A. A.; Kema, IP; Dam, Debby Van; Deyn, PP De

doi:10.1177/1178646920972657

Cited by 12 publications

(11 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Regarding the molecular and biochemical differences underlying these opposing results a straightforward explanation could be that AD mice and LPS treated animals show differences regarding the responsiveness for TDO inhibitory treatment. However, TDO inhibition did not affect kynurenine metabolite levels either in brains of APP23 mice or LPS-treated animals [63,64]. Thus further research is needed in order to clarify the exact mode of action of TDO inhibition on cognitive functions.…”

Section: Tdo and Neurodegenerative Diseasesmentioning

confidence: 94%

“…In recent reports Woodling et al and Sorgdrager and colleagues reported that pharmacological inhibition of TDO improved cognitive performance of APP23 and APP-PS1 AD mice by reversing recognition memory deficits of the animals [62,63]. However, anxiety and cognitive dysfunction provoked with lipopolysaccharide (LPS) stress were not prevented by pharmacological TDO inhibition in this mouse model [64].…”

Section: Tdo and Neurodegenerative Diseasesmentioning

confidence: 96%

See 1 more Smart Citation

Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease

Boros

Vécsei

2021

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

Introduction: Alterations in the activity of tryptophan 2,3-dioxygenase (TDO) cause imbalances in the levels of serotonin and other neuroactive metabolites which can contribute to motor, psychiatric, gastrointestinal, and other dysfunctions often seen in Parkinson's disease (PD). TDO is a key enzyme of tryptophan metabolism at the entry of the kynurenine pathway (KP) which moderates production of neuroactive compounds primarily outside the central nervous system (CNS). Recent data from experimental models indicate that TDO modulation could have beneficial effects on PD symptoms not targeted by traditional dopamine substitution therapies. Areas covered: Based on data available in PubMed and ClinicalTrials databases up until 1 August 2021, we summarize current knowledge of KP alterations in relation to PD. We overview effects of TDO inhibition in preclinical models of neurodegeneration and discuss findings of the impact of enzyme inhibition on motor, memory and gastrointestinal dysfunctions, and neuronal cell loss. Expert opinion: TDO inhibition potentially alleviates motor and non-motor dysfunctions of PD. However, data suggesting harmful effects of long-term TDO inhibition raise concerns. To exploit possibilities of TDO inhibitory treatment, development of further selective TDO inhibitor compounds with good bioavailability features and models adequately replicating PD symptoms of systemic origin should be prioritized.

show abstract

Section: Tdo and Neurodegenerative Diseasesmentioning

confidence: 94%

Section: Tdo and Neurodegenerative Diseasesmentioning

confidence: 96%

Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease

Boros

Vécsei

2021

Expert Opinion on Therapeutic Targets

View full text Add to dashboard Cite

show abstract

“…In turn, preclinical studies indicate that targeting KMO in neurological disorders is a more efficient and safe solution [11,198]. [11,68,151,163,199,200] Indoleamine 2,3-dioxygenase (IDO, EC 1.13.11.17)…”

Section: Kynurenine 3-monooxygenasementioning

confidence: 99%

“…In turn, Kanai et al demonstrated that TDO modulates anxiety-related behavior in mice, while Campesan et al showed that inhibition of TDO activity, by silencing its gene, and protects against the severity of HD symptoms in the transgenic Drosophila melanogaster model [ 163 , 200 , 209 ]. In turn, Sorgdrager et al proved that long-term administration of 680C91, the oral inhibitor of TDO, significantly reversed recognition memory deficits in the mouse model of AD, however without affecting spatial learning and memory or anxiety-related behavior [ 199 ]. Moreover, preclinical studies also found that its inhibition is effective in alleviating depressive symptoms, which are also, to some extent, associated with an increase in oxidative stress levels caused by inflammation and KP overactivity in neurons ( Table 2 ) [ 68 , 151 , 200 ].…”

Section: Enzymes Of the Kynurenine Pathway And The Possibility Of Pharmacological Modulation Of Their Activitymentioning

confidence: 99%

Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Mor

Tankiewicz-Kwedlo

Krupa

et al. 2021

Cells

View full text Add to dashboard Cite

Neurodegenerative disorders are chronic and life-threatening conditions negatively affecting the quality of patients’ lives. They often have a genetic background, but oxidative stress and mitochondrial damage seem to be at least partly responsible for their development. Recent reports indicate that the activation of the kynurenine pathway (KP), caused by an activation of proinflammatory factors accompanying neurodegenerative processes, leads to the accumulation of its neuroactive and pro-oxidative metabolites. This leads to an increase in the oxidative stress level, which increases mitochondrial damage, and disrupts the cellular energy metabolism. This significantly reduces viability and impairs the proper functioning of central nervous system cells and may aggravate symptoms of many psychiatric and neurodegenerative disorders. This suggests that the modulation of KP activity could be effective in alleviating these symptoms. Numerous reports indicate that tryptophan supplementation, inhibition of KP enzymes, and administration or analogs of KP metabolites show promising results in the management of neurodegenerative disorders in animal models. This review gathers and systematizes the knowledge concerning the role of metabolites and enzymes of the KP in the development of oxidative damage within brain cells during neurodegenerative disorders and potential strategies that could reduce the severity of this process.

show abstract

“…Similar to AD patients and Tg2576 mice, APP23 mice exhibit amyloid angiopathy in the cerebral vessels [ 81 ]. Additionally, APP23 Tg mice display age-related abnormal phenotypes associated with cognitive function in various behavioral tests [ 82 , 83 , 84 , 85 , 86 ]. These phenotypes in APP23 mice are similar to all symptoms observed in AD patients.…”

Section: Biomarkers and Amyloid Cascade Hypothesis-related Animal Modelsmentioning

confidence: 99%

Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

Nakai

Yamada

Mizoguchi

2021

IJMS

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is an age-related and progressive neurodegenerative disorder. It is widely accepted that AD is mainly caused by the accumulation of extracellular amyloid β (Aβ) and intracellular neurofibrillary tau tangles. Aβ begins to accumulate years before the onset of cognitive impairment, suggesting that the benefit of currently available interventions would be greater if they were initiated in the early phases of AD. To understand the mechanisms of AD pathogenesis, various transgenic mouse models with an accelerated accumulation of Aβ and tau tangles have been developed. However, none of these models exhibit all pathologies present in human AD. To overcome these undesirable phenotypes, APP knock-in mice, which were presented with touchscreen-based tasks, were developed to better evaluate the efficacy of candidate therapeutics in mouse models of early-stage AD. This review assesses several AD mouse models from the aspect of biomarkers and cognitive impairment and discusses their potential as tools to provide novel AD therapeutic approaches.

show abstract

The Effect of Tryptophan 2,3-Dioxygenase Inhibition on Kynurenine Metabolism and Cognitive Function in the APP23 Mouse Model of Alzheimer’s Disease

Cited by 12 publications

References 75 publications

Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease

Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease

Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Alzheimer’s Disease Animal Models: Elucidation of Biomarkers and Therapeutic Approaches for Cognitive Impairment

Contact Info

Product

Resources

About