Inhibition of Sirt2 Decreases ApoE Secretion in Astrocytes and Microglial Cells

Abstract

Amyloid-β (Aβ) accumulation caused by an imbalance of the production and clearance of Aβ in the brain is associated with the development of Alzheimer's disease (ad). Apolipoprotein E (ApoE) (the strongest genetic risk factor) enhances Aβ clearance, preventing Aβ deposition. Sirtuin 2 (Sirt2) is an NAD+-dependent histone deacetylase and its inhibition has been reported to ameliorate memory impairment in ad-like model mice. However, the role of Sirt2 in ApoE secretion is unknown. Here, we found that inhibition of Sirt2 activity in primary cultured astrocytes and BV2 cells decreased ApoE secretion, resulting in the accumulation of intracellular ApoE and inhibiting extracellular Aβ degradation. However, the reduction of Sirt2 protein level by Sirt2 siRNA decreased ApoE protein level, which ultimately reduces ApoE secretion. In addition, the knockdown of Sirt2 in the HEK293-APP cells also decreased levels of intracellular ApoE leading to reduction of its secretion, which is accompanied by increased Aβ levels without altering APP and APP processing enzymes. Our findings provide a novel role of Sirt2 in ApoE secretion.

Keywords: Alzheimer's disease; Sirt2Abbreviations: ad, Alzheimer’s disease; ABCA1, ATP-binding cassette protein A1; ADAM10, A disintegrin and metalloproteinase domain-containing protein 10; Aβ, Amyloid-beta; APP, Amyloid precursor protein; ApoE, Apolipoprotein E; BACE1, β-site amyloid precursor protein cleaving enzyme 1; IDE, Insulin degrading enzyme; NEP, Neprilysin; PS1, Presenilin 1; Sirt2, Sirtuin 2; amyloid-β; apolipoprotein E; glial cells.