BETA-AMYLOID PRECURSOR PROTEIN-FRAGMENTS AND LYSOSOMAL DENSE BODIES ARE FOUND IN RAT-BRAIN NEURONS AFTER VENTRICULAR INFUSION OF LEUPEPTIN

Infusion of the serine and thiol protease inhibitor, leupeptin, is kno wn to cause a reduction of fast axoplasmic transport, and accumulation of lysosomal dense bodies in neuronal perikarya. We have found these dense bodies in hippocampal and cerebellar neurons contain ubiquitin c onjugated proteins. We now demonstrate that these accumulated neuronal lysosomes are labeled by antisera to the cytoplasmic, transmembrane a nd extracellular domains of beta-amyloid precursor protein (APP) and a lso that lysosomal APP is fragmented. This in vivo model confirms that neurons can process APP via a lysosomal pathway and that neuronal lys osomes in vivo contain both N-terminal and potentially amyloidogenic C -terminal fragments of APP. We also show that increased APP immunoreac tivity after leupeptin treatment is seen first in neurons and later in astrocytes. On recovery from infusion, APP N-terminal immunoreactivit y diminishes whilst C-terminal reactivity remains in neurons. These fi ndings are consistent with production in whole brain of potentially am yloidogenic fragments of APP within neuronal lysosomes in perikarya an d dendrites implying that neurons may play a role in forming the beta- amyloid of plaques.