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- W4328001100 abstract "Amyloid β-protein, Aβ, is normally produced in brain and is cleared by unknown mechanisms. In Alzheimer’s disease (AD), Aβ accumulates in plaque-like deposits and is implicated genetically in neurodegeneration. Here we investigate mechanisms for Aβ degradation and Aβ toxicity in vivo , focusing on the effects of Aβ40, which is the peptide that accumulates in apolipoprotein E4-associated AD. Chronic intraventricular infusion of Aβ40 into rat brain resulted in limited deposition and toxicity. Coinfusion of Aβ40 with the cysteine protease inhibitor leupeptin resulted in increased extracellular and intracellular Aβ immunoreactivity. Analysis of gliosis and TUNEL in neuron layers of the frontal and entorhinal cortex suggested that leupeptin exacerbated Aβ40 toxicity. This was supported further by the neuronal staining of cathepsin B in endosomes or lysosomes, colocalizing with intracellular Aβ immunoreactivity in pyknotic cells. Leupeptin plus Aβ40 caused limited but significant neuronal phospho-tau immunostaining in the entorhinal cortex. Intriguingly, Aβ40 plus leupeptin induced intracellular accumulation of the more toxic Aβ, Aβ42, in a small group of septal neurons. Leupeptin infusion previously has been reported to interfere with lysosomal proteolysis and to result in the accumulation of lipofuscin, dystrophic neurites, tau- and ubiquitin-positive inclusions, and structures resembling paired helical filaments. Coinfusion of Aβ40 with the serine protease inhibitor aprotinin also increased diffuse extracellular deposition but reduced astrocytosis and TUNEL and was not associated with intracellular Aβ staining. Collectively, these data suggest that an age or Alzheimer’s-related defect in lysosomal/endosomal function could promote Aβ deposition and DNA fragmentation in neurons and glia similar to that found in Alzheimer’s disease." @default.
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- W4328001100 date "1998-10-15" @default.
- W4328001100 modified "2023-10-12" @default.
- W4328001100 title "Protease Inhibitor Coinfusion with Amyloid β-Protein Results in Enhanced Deposition and Toxicity in Rat Brain" @default.
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- W4328001100 doi "https://doi.org/10.1523/jneurosci.18-20-08311.1998" @default.
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