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Fly models show kynurenic acid neuroprotection in Alzheimer's and Parkinson's, correlating with mouse data

The amino acid tryptophan is primarily metabolised via the kynurenine biochemical pathway. Several of the compounds that are produced along this pathway, and tryptophan itself, have effects on neuronal survival, some positive, and some negative. It has been speculated that changes in the amounts of these biochemicals might contribute to the pathology of neurodegenerative diseases, with a focus on Huntington's disease. Recent work in Drosophila (Breda et al., 2016) implicates them in Alzheimer's and Parkinson's disease as well.

The neurotoxic members of the kynurenine pathway in mammals are 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), while neuroprotective compounds are tryptophan and kynurenic acid (KYNA). Both 3-HK and QUIN increase the levels of dangerous free radicals that damage proteins and lipids, while KYNA helps remove these free radicals. QUIN and KYNA also have opposing effects - activating and inhibiting activity of the NMDA glutamate receptor respectively - on a signalling pathway that is known to cause cellular damage (so-called excitotoxicity). In Huntington's disease patients and mouse models, 3-HK and QUIN levels are increased in affected parts of the brain, while KYNA levels are decreased.

Drosophila has a simplified version of this pathway, which makes modulation of the levels of these neuroprotective and neurotoxic compounds easier. QUIN is not produced in flies, so the effects of changing relative concentrations of 3-HA and KYNA can be studied more easily. The key enzymes in this pathway are encoded by the well-known eye colour genes vermilion and cinnabar. Previous work (Campesan et al., 2011) showed that reducing the expression of vermilion and cinnabar made a mutant huntingtin protein fragment - the active toxic molecule in Huntington's disease - less toxic, so that there was less damage to neurons. Oxenkrug et al. also showed that inhibiting enzymes in the fly kynurenine pathway increased life span. Breda et al now report studies of flies with 20x higher than normal KYNA levels and found strong reductions in nerve cell damage in a Huntington's disease model.

Importantly, Breda et al., have now studied the effects of varying the neurotoxic/neuroprotective compound output ratio from the kynurenine pathway on the behaviour and survival of Drosophila Alzheimer's and Parkinson's models (targeted overexpression of Abeta42 or Abeta42Arctic for Alzheimer's, and of alpha-Synuclein for Parkinson's). This was achieved both by RNAi silencing of the vermilion and cinnabar genes and by pharmacological inhibition of an enzyme in the pathway. They found that shifting the ratio in favour of KYNA (neuroprotective) improved motor phenotypes and increased longevity of both Alzheimer's and Parkinson's flies.

These observations in flies correlate with rodent studies. Zwilling et al showed that raising blood KYNA levels by inhibition of the enzyme that catalyses the production of 3-HK from kynurenine reduced neurodegeneration in a mouse model of Alzheimer's disease (J20 mice, Mucke et al.), preventing the development of spatial memory deficits, anxiety-related behaviour and loss of synapses. Interestingly, the inhibitor used does not cross the blood brain barrier, whereas KYNA does, so peripheral increases in KYNA can ameliorate neurodegeneration.

Therefore the new data of Breda et al. provide further evidence that pharmacological inhibition of enzymes in the kynurenine pathway may be beneficial for human Alzheimer's and Parkinson's disease patients. Since crystal structures of several key enzymes have been determined (Huang et al., 2013; Amaral et al., 2013), the way is open to new drug design. These data also show that fly studies give the same results as mouse studies, in a system that is much more suitable for drug screening.

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