Abstract
Despite the fact that harboring the apolipoprotein E4 (APOE4) allele represents the single greatest risk factor for late-onset Alzheimer's disease (AD), the exact mechanism by which apoE4 contributes to disease progression remains unknown. Recently, we demonstrated that a 151 amino-terminal fragment of apoE4 (nApoE41-151) localizes within the nucleus of microglia in the human AD brain, suggesting a potential role in gene expression. In the present study, we investigated this possibility utilizing BV2 microglia cells treated exogenously with nApoE41-151. The results indicated that nApoE41-151 leads to morphological activation of microglia cells through, at least in part, the downregulation of a novel ER-associated protein, CXorf56. Moreover, treatment of BV2 cells with nApoE41-151 resulted in a 68-fold increase in the expression of the inflammatory cytokine, TNFα, a key trigger of microglia activation. In this regard, we also observed a specific binding interaction of nApoE41-151 with the TNFα promoter region. Collectively, these data identify a novel gene-regulatory pathway involving CXorf56 that may link apoE4 to microglia activation and inflammation associated with AD.
Highlights
Alzheimer’s disease (AD) currently has a significant global impact
The purpose of the current study was to elucidate the possible functional consequences of nuclear trafficking by nApoE41-151 with our major hypothesis being the fragment acts as an enhancer or a repressor of gene transcription
All experiments were performed on BV2 microglia cells due to the fact that nuclear localization of nApoE41-151 would be necessary a priori in order for the fragment to regulate gene transcription directly
Summary
Alzheimer’s disease (AD) currently has a significant global impact. In the USA alone, over 5.7 million Americans suffer from this progressive, irreversible brain disorder that destroys memory and thinking skills [1]. Evidence documented for the past 30 years has proven the existence of inflammation in AD, including activated microglia within and surrounding senile plaques [2,3,4,5]. Despite this wealth of evidence, the stimuli that led to microglia activation and subsequent inflammation in AD are not well described. The APOE4 allele represents the single greatest risk factor for late-onset AD, and inheritance of one copy of the APOE4 allele increases Alzheimer’s disease (AD) risk fourfold, while two copies raises the risk tenfold [6]. A recent study linking apoE4 to neuroinflammation in AD demonstrated that apoE4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment and this in turn may promote neuroinflammation in AD [7]
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