IC‐P‐097: Proteasome inhibition increases Aβ load and the underlying mechanisms in rat brain

Accumulation of β-amyloid (Aβ) is an important hallmark lesion of Alzheimer's disease (AD). Studies suggest that alterations in ubiquitin proteasome system (UPS) may be involved in AD pathologies, and proteasome activity is also decreased in the brain regions, such as the hippocampus, that are more susceptible to the AD pathology. However, the role of proteasome in the proteolysis of Aβ is still uncertain. To explore the role of proteasome in Aβ accumulation of AD pathologies, we investigated here the influence of proteasome inhibition on Aβ production and the underlying mechanisms in rats. We injected bilaterally lactacystin, an irreversible inhibitor of proteasome, into the rat hippocampus and employed Western blotting, immunohistochemistry, and enzyme linked immunosorbent assay (ELISA) to measure the alterations of Aβ production and the possible mechanisms in rats. We observed the following results in our experiment. (1) Lactacystin inhibited the proteasome activities; (2) After proteasome inhibition, the level of Aβ40 and Aβ42 were both increased by ELISA, and Aβ fragments were also increased by Wesstern blotting and immunohistochemstry with 4G8 and 6E10; (3) APP levels including full length and C-Terminal fragment cleaved by β-secretase (CTF-β) were elevated upon proteasome inhibition; (4) BACE1, PS-1 and PS-2 were increased at the different time points, witch suggested that β-secretase and γ-secretase activity were increased after proteasome inhibition. We conclude that proteasome inhibition led to the increase of Aβ production through elevating APP level and the β- and γ-secretase activities in rat brain.