ApoE isoforms and carboxyl-terminal-truncated apoE4 forms affect neuronal BACE1 levels and A beta production independently of their cholesterol efflux capacity

作者：Dafnis Ioannis; Raftopoulou Christina; Mountaki Christina; Megalou Evgenia; Zannis Vassilis I; Chroni Angeliki^*

来源：Biochemical Journal, 2018, 475(10): 1839-1859.

DOI：10.1042/BCJ20180068

The beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) initiates the production of amyloid-beta peptide (A beta), which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect A beta metabolism. Cholesterol homeostasis is maintained in the brain by apolipoprotein E (apoE). The apoE4 isoform constitutes the major risk factor for AD. Here, we investigated the effect of apoE forms on A beta generation and on BACE1 levels. We also examined the potential involvement in these processes of cholesterol transporters ABCG1 and ABCG4 or the lipoprotein receptor SR-BI, which are implicated in cholesterol efflux to apoE. It was found that reconstituted lipoprotein-associated apoE isoforms promoted the increase of A5 production and oligomerization and of BACE1 levels in human neuroblastoma SK-NSH cells, with an apoE4 >= apoE3 > apoE2 potency rank order. Progressive carboxyl-terminal apoE4 deletions between residues 230-299 decreased the protein's ability to increase BACE1, while further truncations up to residue 166 prevented apoE4 from increasing BACE1 and A beta levels in SK-N-SH and primary mouse neuronal cells. ABCG1, but not ABCG4 or SR-BI, moderately increased A beta production and BACE1 levels in SK-NSH cells. All apoE forms affected A beta production/oligomerization and BACE1 levels in a pattern that did not follow that of their capacity to promote ABCG1, ABCG4 or SR-BImediated cholesterol efflux. Overall, our data indicate that apoE-containing lipoprotein particles can have a direct effect on BACE1 levels and A beta secretion and possibly contribute to AD pathogenetic processes, independently of their capacity to promote cholesterol efflux.

• 出版日期2018-5-31