Suppression of amyloid-b secretion from neurons by cis-9, trans-11-octadecadienoic acid, an isomer of conjugated linoleic acid

Abstract

C9,t11CLA significantly suppressed generation of Aβ in primary cultures of mouse neurons. CLA treatment did not affect the levels of β-site APP-cleaving enzyme 1 (BACE1), a component of active γ-secretase complex presenilin 1 amino-terminal fragment (PS1 NTF), or Aβ protein precursor (APP) in cultured neurons. BACE1 activity in lysate of neurons treated with c9,t11 CLA, but not t10,c12 CLA, decreased slightly, although c9,t11 CLA did not directly affect the activity of recombinant BACE1. Interestingly, localization of BACE1 and APP in early endosomes increased in neurons treated with c9,t11 CLA; concomitantly, the localization of both proteins was reduced in late endosomes, where APP is predominantly cleaved by BACE1. c9,t11 CLA and t10,c12 CLA appeared to be incorporated into membrane phospholipids, as the level of CLA-containing ysophosphatidylcholine (CLA-LPC) increased dramatically in neurons incubated with CLA. Taken together, our findings indicate that accumulation of c9,t11 CLA-LPC, but not t10,c12 CLA-LPC, in neuronal membranes suppresses amyloidogenic cleavage of APP, thereby contributing to preservation of brain neurons by suppressing neurotoxic Aβ production in aged subjects.