Abstract
An inhibitor of cathepsins B and L was used to test if lysosomal dysfunction in cultured slices of rat frontal cortex induces pathological features that develop in the human cortex during aging and Alzheimer's disease (AD). Incubation for 6 days withN-CBZ-l-phenylalanyl-l-alanine-diazomethylketone (ZPAD) resulted in a massive proliferation of endosomes-lysosomes in all cortical layers. Slices additionally exposed to a washout of 4 days had numerous meganeurites, blister-like structures in the region of the axon hillock, in layer III but not in other cortical laminae. Meganeurites are a characteristic feature of the human frontal cortex after age 50 and are largely restricted to layer III. Tests for apoptosis were carried out at two intervals following meganeurite formation. TUNEL-labeled neurons were confined to layers II/III on the surface of the slices but there was no evidence for a ZPAD effect. In all, 6 days of lysosomal dysfunction reproduces characteristic effects of normal aging in neocortex without generating some key features of AD.
Highlights
Large fusiform expansions interposed between the base of the perikaryon and the initial portion of the axon commonly occur in areas of the aged human brain [5]
Slices obtained from the frontal cortex and maintained in vitro for 15–21 days had laminar cytoarchitectural features similar to those found in vivo [8, 9, 11]
Increased numbers of endosomes-lysosomes were evident in all layers of cortex following 6 days of treatment with the cathepsin B and L inhibitor
Summary
Large fusiform expansions interposed between the base of the perikaryon and the initial portion of the axon commonly occur in areas of the aged human brain [5] These ‘‘meganeurites’’ are present in frontal cortex by age 50, increase in number to at least age 70, are prominent in layer III pyramidal cells but not in neurons of other cortical lamina, and are filled with lipofuscin and other complex lysosomal organelles [5]. The location and appearance of meganeurites suggest that lysosomes gradually accumulate during human aging within abnormal processes that can negatively affect the integrity of somatoaxonal communication Their origins, and the reasons meganeurites develop in only select collections of neurons, are questions of considerable interest. Between 1 and 2 weeks later, meganeurites of the type found in the human brain—but not reported for rats— were observed in the CA1 subfield [3] This event was correlated with a marked reduction in lysosomes in the somata of meganeurite containing pyramidal cells. It appeared that meganeurites were generated by accumulations of excess lysosomes transported to the basal pole of neurons
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