A Fragment of Apolipoprotein E4 Leads to the Downregulation of a CXorf56 Homologue, a Novel ER-Associated Protein, and Activation of BV2 Microglial Cells.
Tanner B PollockJacob M MackRyan J DayNoail F IshoRaquel J BrownAlexandra E OxfordBrad E MorrisonEric J HaydenTroy T RohnPublished in: Oxidative medicine and cellular longevity (2019)
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.
Keyphrases
- induced apoptosis
- inflammatory response
- gene expression
- cell cycle arrest
- late onset
- cognitive decline
- neuropathic pain
- oxidative stress
- lipopolysaccharide induced
- signaling pathway
- lps induced
- rheumatoid arthritis
- dna methylation
- endoplasmic reticulum stress
- cell proliferation
- poor prognosis
- cell death
- spinal cord injury
- transcription factor
- metabolic syndrome
- multiple sclerosis
- resting state
- big data
- blood brain barrier
- dna binding
- cerebral ischemia
- combination therapy
- subarachnoid hemorrhage
- replacement therapy