Lysosomal dysfunction results in lamina-specific meganeurite formation butnot apoptosis in frontal cortex

An inhibitor of cathepsins B and L was used to test if lysosomal dysfunctio n in cultured slices of rat frontal cortex induces pathological features th at develop in the human cortex during aging and Alzheimer's disease (AD). I ncubation for 6 days with N-CBZ-L-phenyl-alanyl-L-alanine-diazomethylketone (ZPAD) resulted in a massive proliferation of endosomes-lysosomes in all c ortical layers. Slices additionally exposed to a washout of 4 days had nume rous meganeurites, blister-like structures in the region of the axon hilloc k, in layer III but not in other cortical laminae. Meganeurites are a chara cteristic feature of the human frontal cortex after age 50 and are largely restricted to layer III. Tests for apoptosis were carried out at two interv als 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 characteri stic effects of normal aging in neocortex without generating some key featu res of AD. (C) 1999 Academic Press.