Recent evidence, based upon immunocytochemical and histochemical analysis of brain cortical tissue from
alzheimer's disease patients, has suggested that altered activity and/or distribution of the lysosomal
proteases cathepsins B and D may be implicated in the abnormal
protein processing pathway resulting in formation of the neurotoxic
amyloid A4
peptide, characteristic of this
neurodegenerative disorder. We have therefore compared, via biochemical assay techniques using conventional or specially synthesised (corresponding to
protein cleavage points of relevant to A4
peptide formation)
fluorogenic substrates, the levels of activity of the lysosomal
proteases cathepsins B, D, H and L, and dipeptidyl
aminopeptidases I and II in frontal cortex (grey/white matter) from control and
Alzheimer's disease patients. For comparative purposes, activity levels of the above
enzymes were also determined in frontal cortex tissue from cases with
Lewy body dementia and
Parkinson's disease, and in caudate tissue from control and
Huntington's disease cases. There was no significant difference in activity for any
protease types in tissue from control cases and cases with
Alzheimer's disease,
Lewy body dementia or
Parkinson's disease, with the exception of reduced
dipeptidyl aminopeptidase II activity in
Lewy body dementia and Parkinson's cases. We have therefore been unable to confirm a potential role for lysosomal
cathepsins in the characteristic neurodegeneration associated with
Alzheimer's disease; however the finding of significant increases in activity of
dipeptidyl aminopeptidase II,
cathepsin H and
cathepsin D specifically in cases with
Huntington's disease is of particular note. We therefore suggest the potential role of the latter
enzymes in the pathogenesis of
Huntington's disease requires further investigation.