INCREASED MONOAMINE-OXIDASE-B ACTIVITY IN PLAQUE-ASSOCIATED ASTROCYTES OF ALZHEIMER BRAINS REVEALED BY QUANTITATIVE ENZYME AUTORADIOGRAPHY

The aetiology and pathogenesis of Alzheimer's disease are currently po orly understood, but symptomatic disease is associated with amyloid pl aques, neurofibrillary tangles, neuronal loss and numerous alterations of neurotransmitter systems in the CNS. Monoamine oxidase type B is k nown to be increased in Alzheimer diseased brains. The distribution an d abundance of catalytic sites for monoamine oxidases A and B in post mortem human brains of 11 Alzheimer disease cases and five age-matched controls were investigated by quantitative enzyme radioautography. Us ing tritiated monoamine oxidase inhibitors (Ro41-1049 and lazabemide)- as high affinity substrates selective for monoamine oxidases A and B, respectively-it was found that monoamine oxidase B activity increased up to three-fold exclusively in temporal, parietal and frontal cortice s of Alzheimer disease cases compared with controls. This increase was restricted to discrete patches (similar to 185 mu m in diameter) whic h occupied approximately 12% of the cortical areas examined. In other brain regions (hippocampal formation>>caudate-putamen>cerebellum), pat ches of [H-3]lazabemide-enriched binding were less abundant. [H-3]Ro41 -1049 binding (i.e. monoamine oxidase A) was unchanged in all tissues of diseased versus control brains. The monoamine oxidase B-enriched pa tches in all cortical regions correlated, in their distribution and fr equency, with glial fibrillary acidic protein-immunoreactive clusters of astrocytes. Diffuse and mature beta-amyloid-immunoreactive senile p laques as well as patches of high density binding of [H-3]PK-11195-a h igh-affinity ligand for peripheral-type (mitochondrial) benzodiazepine binding sites in microglia/macrophages-were found throughout Alzheime r diseased cortices. The up-regulation of monoamine oxidase B in plaqu e-associated astrocytes in Alzheimer's disease-in analogy to its propo sed role in neurodegenerative disorders such as Parkinson's disease-mi ght, indirectly, be a potential source of cytotoxic free radicals. Laz abemide, a selective reversible monoamine oxidase B inhibitor, is curr ently under clinical evaluation for the treatment of Parkinson's and A lzheimer's diseases. We conclude that enzyme radioautography with [H-3 ]lazabemide is a reliable high resolution assay for plaque-associated astroglioses in Alzheimer's disease. Its clinical diagnostic utility f or positron emission tomography or single photon emission computer tom ography studies is being investigated.