Huntington's Disease (HD) and Alzheimer's disease (AD) are neurodegenerative disorders characterizedby the accumulation of misfolded proteins. Sadly, many years of research into the mechanisms ofneurodegeneration have failed to produce effective therapies that halt or reverse these diseases. Werecently completed a genomic screen in S. cerevisiae with single gene deletion strains that identifiedkynurenine 3-monooxygenase (KMO), an enzyme in the kynurenine pathway (KP) of tryptophandegradation, as a potent suppressor of mutant huntingtin (htt) toxicity. The brain levels of two neurotoxicmetabolites in the KP, quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK), are increased in the striatumand neocortex in early grade HD; similar increases in QUIN and/or 3-HK are present in three mouse modelsof HD. We show that brain levels of QUIN are increased in the hippocampus and entorhinal cortex of mousemodels of AD, but not in the striatum or other unaffected brain regions. QUIN and 3-HK have long beenhypothetically linked to the pathophysiology of neurological diseases including HD and AD. Indeed,intrastriatal injection of QUIN together with 3-HK causes striatal lesions resembling those found in HD thatmay be mediated by the combination of A/-methyl D-aspartate (NMDA) receptor over-stimulation(excitotoxicity) and free radical formation. Subchronic intraventricular infusion of QUIN in rats producesbiochemical changes and memory deficits that may share similarities with those found in AD patients. In ourproposal, we present data showing that treatment of a mouse model of HD with Ro 61-8048, a high-affinity,orally bioavailable, small-molecule inhibitor of KMO, improved multiple behavioral outcome measuresdespite the fact that this compound displayed marginal penetration across the blood brain barrier (BBB). Werecently generated a novel series of brain penetrating KMO inhibitors and mice that carry a conditional nullallele of Kmo. With these tools in hand, we are for the first time in a position to test rigorously if the microglialKP and excitotoxicity play important roles in mouse models of HD and AD. The following specific aims willbegin to test the hypothesis that microglial derived increases in neurotoxic KP metabolites occur in distinctbrain microenvironments in a manner that contributes to selective neuronal vulnerability in mouse models ofHD and AD:
AIM 1. To determine if genetic and pharmacological inhibition of KMO in microglia improvesbehavioral and pathological outcome measures in mouse models of HD and AD;
AIM 2. To identify theregulatory elements and signal transduction pathways that mediate mutant huntingtin (htt)/amyloid (3-protein(A|3)-induced KP activation in microglia;
AIM 3. To determine the cellular mechanisms that mediateincreases in toxic microglial KP metabolites in discrete brain microenvironments in a mouse model of HD. Insummary, these experiments will determine if pharmacological inhibition of KMO may be a bona fidetherapeutic approach to treating HD and AD.
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