Cortical Glutaminase , ( 3-Glucuronidase and Glucose Utilization in Alzheimer ' s Disease

Large pyramidal neurons of rat and human neocortex stain immunohistochemically for phosphate-activated glutaminase (PAG). In a limited number of postmortem brains, we find large reductions in cortical PAG activity in Alzheimer's disease (AD). This finding is consistent with histological evidence that pyramidal neurons are affected in AD. The reductions are greater than those found in the same samples in choline acetyltransferase (ChAT) but the possible deleterious effects of coma and similar premortem factors on human PAG activity have yet to be assessed. The activity of (J-glucuronidase, a lysosomal enzyme which occurs in reactive astrocytes, is elevated in the same samples. Positron emission tomography (PET) studies, using F-fluorodeoxyglucose (FDG), have demonstrated significant deficiencies in glucose metabolism in the cortex in AD, with the parietal, temporal and some frontal areas being particularly affected. We found in serial scans of 13 AD cases, including one relatively young (44-46 year old) familial case, an exacerbation of the defect over time in most cases. We have found a negative correlation between the regional metabolic rates for glucose (LCMR(s)) measured premortem and the (J-glucuronidase activities measured postmortem on a few AD cases that have come to autopsy. The correlations between LCMR(s) and PAG and ChAT activities tend to be positive. The results are consistent with previous suggestions that decreased LCMR(s) in AD reflect local neuronal loss and gliosis. RESUME: La glutaminase corticate, la-Glucuronidase et ('utilisation du glucose dans la maladie d'Alzheimer Les gros neurones pyramidaux du neocortex du rat et de l'humain captent la coloration immunohistochimique pour la glutaminase active^ au prosphate (PAG). Dans un petit nombre de cerveaux preleves a l'autopsie, nous observons des diminutions considerables dans l'activit6 corticale de la PAG dans la maladie d'Alzheimer (MA). Cette observation est compatible avec le fait que les neurones pyramidaux sont atteints dans la MA. Les diminutions sont plus grandes que celles que Ton retrouve dans les memes echantillons pour l'acetyltransferase de la choline (ChAT). Cependant, les effets neTastes possibles du coma et de ph6nomenes premortem similaires sur l'activit6 de la PAG humaine n'ont pas encore 6t6 evalu6s. L'activity de la p-glucuronidase, un enzyme lysosomial qu'on retrouve dans astrocytose reactionnelle, est elevee dans ces 6chantillons. Les etudes effectuees par tomographic par emission de positrons (PET) utilisant le F-fluorodeoxyglucose (FDG), ont montre des deficiences significatives du metabolisme du glucose dans le cortex des patients atteints de MA, les zones parietales, temporales et certaines zones frontales dtant particulierement atteintes. Nous avons observe' lors de scans seYifis chez 13 cas de MA, incluant un cas familial relativement jeune (4446 ans), une exacerbation du defaut au cours du suivi chez la plupart des cas. Nous avons etabli qu'il existe une correlation negative entre les taux m£taboliques r6gionaux du glucose (LCMR(s)) mesur6s premortem et l'activitd de la Pglucuronidase mesuree postmortem chez quelques cas de MA ayant subi une autopsie. La correlation entre les LCMR(s) et l'activite de la PAG et de la ChAT avait tendance a etre positive. Les r£sultats sont compatibles avec des suggestions faites precedemment selon lesquelles une diminution des LCMR(s) dans la MA reflete une perte neuronale locale et un processus de gliose. Can. J. Neurol. Sci. 1989; 16:511-515 Morphological data on the distribution of plaques and tangles in Alzheimer's disease (AD) suggest that an important part of the pathology may be a degeneration of the pyramidal neurons forming corticocortical association projections." There is considerable evidence that these neurons may use glutamate as their excitatory transmitter. They stain heavily for glutamate' and retrogradely transport D-[H]aspartate; moreover, there is loss of high affinity [H]glutamate uptake in the projecting nerve endings following axotomy.' More recently, in rat and human cortex and in rat and guinea pig hippocampus," they have been shown to stain immunohistochemically for phosphate-activated glutaminase (PAG), a mitochondrial enzyme which catalyzes the hydrolysis of glutamine to glutamate and ammonia. PAG has been suggested as a possible mediator of the synthesis From the Kinsmen Laboratory of Neurological Research, Dept. of Psychiatry, University of B.C., Vancouver (EGM, PLM and HA), and the School of Computer Science, Burnaby (RH), B.C. Reprint requests to: Dr. Edith McGeer, Kinsmen Laboratory of Neurological Research, University of B.C., 2255 Westbrook Mall, Vancouver, B.C., Canada V6T 1W5