The hAPP KM670/671NL x TDO knockout mouse model: genetic interference with tryptophan metabolism and proteome ageing in neurodegeneration.

RNA interference-based studies in C. elegans indicated that tryptophan 2,3-dioxygenase (TDO) depletion strongly suppressed proteotoxicity of several aggregation-prone proteins independently of kynurenine metabolites, and moreover positively affected life span of the nematodes. Therefore, we propose that TDO functions as a general regulator of protein toxicity, and hypothesize that increased TDO expression in the brain contributes to the pathophysiology of Alzheimer's disease in particular, and neurodegenerative diseases in general. Interfering with TDO activity might offer novel therapeutic avenues for treating or preventing age-related neurodegenerative diseases. We want to determine whether inhibition of tryptophan degrading pathways reduces age-dependent cognitive decline and behavioural alterations, as well as CNS amyloid deposition in a relevant mouse model for Alzheimer's disease. Genetic depletion of TDO will be accomplished by crossing the APP23 amyloidosis mouse model with a TDO-knockout mouse. The four genotypes of interest are: TDO knockout APP23 mice, TDO knockout (wild-type) mice, TDO-expressing APP23 and wild-type control mice. TDO and its functional homologue indoleamine 2,3-dioxygenase are the first and rate-limiting enzymes in the evolutionary conserved kynurenine pathway. Since growing evidence implicates kynurenine pathway metabolites in the development and progression of Alzheimer's disease, kynurenine pathway metabolites will be determined in CSF, serum and brain tissue of the different genotypes.

Keywords:MOUSE MODELS, KYNURENINE, ALZHEIMER'S DISEASE, TRYPTOFAAN

Disciplines:Laboratory medicine, Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing