Research ReportSubcellular compartmentalization of proteolytic enzymes in brain regions and the effects of chronic β-amyloid treatment

Amyloid β-protein (Aβ) is the major amyloid component of toxic amyloid senile plaques inducing slow neuronal degeneration in brains of Alzheimer's patients. It can induce proteolysis of some cytoskeletal proteins in the neuron; however, studies of proteolytic enzyme activity in different brain regions and their subcellular compartmentalization were not carried out. In this work, the effects of chronic intracerebroventricular administration of Aβ25-35 on proteolytic enzymes in subcellular fractions from rat brain regions were studied. Mitochondrial and cytosolic caspase-9 and caspase-3 activities in neocortex, cerebellum, and hippocampus were shown to be increased during infusion of Aβ25-35. In Aβ25-35-treated rats, cytosolic calcium-dependent thiol proteases calpain-1 and calpain-2 appeared in mitochondria and lysosomes, causing apparent release of lysosomal cathepsins B and D to mitochondria and of β-galactosidase to the cytosol. The increase in all proteolytic activities in brain subcellular fractions under the influence of administered Aβ suggests that these enzymes could be transferred across intracellular membranes and involved in neurodegeneration.

Research Highlights►Proteolytic and glycolytic enzymes in brain regions are compartmentalized. ►Neocortex, cerebellum, and hippocampus differ in proteolysis comparmentalization. ►Chronic treatment of rats with β-amyloid leads to activation of caspases-3 and -9. ►β-Amyloid promotes transfer of calpains to mitochondria and lysosomes. ►β-Amyloid promotes efflux of cathepsins B and D and glycosidases from lysosomes.