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 are involved in a variety of neurodegenerative disorders. The purpose of the present study was to investigate the biosynthetic machinery of KYNA in several regions of Alzheimer's disease (AD) brain. The endogenous levels of L-KYN, 3-OH-KYN and KYNA in frontal cortex, caudate nucleus, putamen, hippocampus, and cerebellum of 11 autopsy confirmed cases of AD and 13 age-matched controls were analyzed. Subsequently, the activity of two proteins responsible 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 nucleus of AD, by 192 and 177%, respectively. In other areas of AD brain only a minor 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 measured only in the caudate nucleus of AD subjects. Kinetic analysis of KAT I and II performed in the caudate nucleus of AD patients revealed a marked increase of Vmax, by 207 and 274% of controls, respectively. Km value for L-KYN using pyruvate as amino acceptor was significantly higher for KAT II (247% of controls). The present data indicate an elevated kynurenine metabolism 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.
Baran
H
H
Ludwig Boltzmann Institute of Clinical Neurobiology, Psychiatric Hospital Vienna, Austria.
Jellinger
K
K
Deecke
L
L
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D002421:Caudate Nucleus / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D007736:Kynurenic Acid / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism*; D008190:Lyases / Q000378:metabolism; D008297:Male; D016555:Matched-Pair Analysis; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D000637:Transaminases / Q000378:metabolism
D007737:Kynurenine; D019289:Pyruvic Acid; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D008190:Lyases; D007736:Kynurenic Acid