Protease Inhibitor Coinfusion with Amyloid β-Protein Results in Enhanced Deposition and Toxicity in Rat Brain

摘要: Amyloid β-protein, Aβ, is normally produced in brain and cleared by unknown mechanisms. In Alzheimer’s disease (AD), Aβ accumulates plaque-like deposits implicated genetically neurodegeneration. Here we investigate mechanisms for degradation toxicity vivo , focusing on the effects of Aβ40, which peptide that apolipoprotein E4-associated AD. Chronic intraventricular infusion Aβ40 into rat resulted limited deposition toxicity. Coinfusion with cysteine protease inhibitor leupeptin increased extracellular intracellular immunoreactivity. Analysis gliosis TUNEL neuron layers frontal entorhinal cortex suggested exacerbated This was supported further neuronal staining cathepsin B endosomes or lysosomes, colocalizing immunoreactivity pyknotic cells. Leupeptin plus caused but significant phospho-tau immunostaining cortex. Intriguingly, induced accumulation more toxic Aβ42, a small group septal neurons. previously has been reported to interfere lysosomal proteolysis result lipofuscin, dystrophic neurites, tau- ubiquitin-positive inclusions, structures resembling paired helical filaments. serine aprotinin also diffuse reduced astrocytosis not associated staining. Collectively, these data suggest an age Alzheimer’s-related defect lysosomal/endosomal function could promote DNA fragmentation neurons glia similar found disease.