Kynurenine metabolism in Alzheimer's disease

L-kynurenine (L-KYN) serves as a substrate for the synthesis of neurotoxic 3-OH-kynurenine (3-OH-KYN) and neuroprotective kynurenic acid (KYNA). KYNA is able to interact with ionotropic excitatory amino acid receptors that ar e involved in a variety of neurodegenerative disorders. The purpose of the present study was to investigate the biosynthetic machinery of KYNA in seve ral regions of Alzheimer's disease (AD) brain. The endogenous levels of L-K YN, 3-OH-KYN and KYNA in frontal cortex, caudate nucleus, putamen, hippocam pus, and cerebellum of 11 autopsy confirmed cases of AD and 13 age-matched controls were analyzed. Subsequently, the activity of two proteins responsi ble for the production of KYNA, kynurenine aminotransferases I and II (KAT I and KAT II), was investigated. There was a trend for a decrease of L-KYN and 3-OH-KYN in all examined regions of AD brain, as compared to controls. However, KYNA was increased significantly in the putamen and caudate nucleu s of AD, by 192 and 177%, respectively. In other areas of AD brain only a m inor increase of KYNA was present. Elevated KYNA in the caudate nucleus and putamen correlated with a significant increase of KAT I activities in both nuclei - 157 and 147%, respectively. A minor increase of KAT II was measur ed only in the caudate nucleus of AD subjects. Kinetic analysis of KAT I an d II performed in the caudate nucleus of AD patients revealed a marked incr ease of V-max, by 207 and 274% of controls, respectively. K-m value for L-K YN using pyruvate as amino acceptor was significantly higher for KAT II (24 7% of controls). The present data indicate an elevated kynurenine metabolis m in AD brain. A marked increase of KYNA in the caudate nucleus and putamen may compensate the hyperactivity of the striato-frontal loop in AD brains. Blockade of NMDA receptors by KYNA may be responsible for impaired memory, learning and cognition in AD patients.