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

ApoE isoforms and carboxyl-terminal truncated apoE4 forms affect neuronal BACE1 levels and Aβ production independently of their cholesterol efflux capacity. Biochem J. 2018 May 09;: Authors: Dafnis I, Raftopoulou C, Mountaki C, Megalou E, Zannis VI, Chroni A Abstract The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates the production of amyloid-beta peptide (Aβ) which is central to the pathogenesis of Alzheimer's disease (AD). Changes in brain cholesterol homeostasis have been suggested to affect Aβ 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 Aβ 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 that are implicated in cholesterol efflux to apoE. It was found that reconstituted lipoprotein-associated apoE isoforms promoted the increase of Aβ production and oligomerization and of BACE1 levels in human neuroblastoma SK-N-SH 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 Aβ levels in SK-N-SH and primary mouse neuronal...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research