The aetiology and pathogenesis of
Alzheimer's disease are currently poorly understood, but symptomatic disease is associated with
amyloid plaques, neurofibrillary tangles, neuronal loss and numerous alterations of
neurotransmitter systems in the CNS.
Monoamine oxidase type B is known to be increased in Alzheimer diseased brains. The distribution and 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. Using 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 cortices of
Alzheimer disease cases compared with controls. This increase was restricted to discrete patches (approximately 185 microns in diameter) which occupied approximately 12% of the cortical areas examined. In other brain regions (hippocampal formation >> caudate-putamen > cerebellum), patches of [3H]
lazabemide-enriched binding were less abundant. [3H]Ro41-1049 binding (i.e.
monoamine oxidase A) was unchanged in all tissues of diseased versus control brains. The
monoamine oxidase B-enriched patches in all cortical regions correlated, in their distribution and frequency, with
glial fibrillary acidic protein-immunoreactive clusters of astrocytes. Diffuse and mature
beta-amyloid-immunoreactive
senile plaques as well as patches of high density binding of [3H]
PK-11195--a high-affinity
ligand for peripheral-type (mitochondrial)
benzodiazepine binding sites in microglia/macrophages--were found throughout Alzheimer diseased cortices. The up-regulation of
monoamine oxidase B in plaque-associated astrocytes in
Alzheimer's disease--in analogy to its proposed role in
neurodegenerative disorders such as
Parkinson's disease--might, indirectly, be a potential source of cytotoxic
free radicals.
Lazabemide, a selective reversible
monoamine oxidase B inhibitor, is currently under clinical evaluation for the treatment of Parkinson's and
Alzheimer's diseases. We conclude that
enzyme radioautography with [3H]
lazabemide is a reliable high resolution assay for plaque-associated astroglioses in
Alzheimer's disease. Its clinical diagnostic utility for positron emission tomography or single photon emission computer tomography studies is being investigated.