A Dual Role for Apolipoprotein E in Neuroinflammation: Anti- and Pro-Inflammatory Activity

Abstract

Chronically activated glia associated with amyloid plaques might contribute to neuronal dysfunction in Alzheimer's disease (AD) through generation of neuroinflammatory molecules. Apolipoprotein E (apoE), also found associated with amyloid plaques, has been hypothesized to serve an anti-inflammatory role in the CNS through its ability to modulate beta-amyloid (Abeta)-induced glial activation. To further characterize the effect of apoE on inflammation, we examined the ability of exogenously added human apoE3 and apoE4 to modulate neuro inflammatory responses of cultured rat glia. Apolipoprotein E3 (apoE3) and apoE4 suppressed oligomeric Abeta-induced production of inducible nitric oxide synthase and cyclo-oxygenase-2, supporting an anti- inflammatory role for apoE. Exogenous apoE also inhibited Abeta-induced production of endogenous apoE. However, exogenous apoE in the absence of Abeta stimulated production of the pro-inflammatory cytokine interleukin-1beta in an isoform-dependent manner, with apoE4 inducing a significantly greater response than apoE3. These data support the idea that Abeta stimulation of glial apoE limits neuroinflammation but that overproduction of apoE by activated glia might exacerbate inflammation. In addition, the observation that apoE4 has more robust pro-inflammatory activity than apoE3 provides a mechanistic link between the APOE4 allele and AD, and suggests potential apoE-based therapeutic strategies.

ApoE4 upregulates the activity of mitochondria‐associated ER membranes

“…Amyloid‐dependent theories make use of the fact that ApoE, either by direct binding to Aβ 42 or by competition with Aβ receptors, such as the lipoprotein receptor‐related protein‐1 43, is able to modify Aβ production 44 or clearance 45. Amyloid‐independent theories implicate the cytotoxicity of ApoE4 fragments 46, its role in cholesterol homeostasis 35, neuroprotection/apoptosis 20, neurite outgrowth 19, inflammation 47, and vascular integrity 48. AD is clearly a multifaceted disease, with changes in amyloid metabolism occurring alongside these amyloid‐unrelated phenomena.…”

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

“…CRP is an important regulator of immune responses and it is commonly used as a biomarker for systemic inflammation. The presence of the APOE ε 4 allele has been suggested to promote a pro‐inflammatory state in comparison to other APOE alleles 3, 4, 5. Thus, it is surprising that lower hs‐CRP levels, indicating lower levels of inflammation, are repeatedly detected among the individuals with the risk‐conferring APOE ε 4 allele.…”

“…The presence of the APOE ε 4 allele considerably increases the risk and lowers the age of onset of AD, while the APOE ε 2 allele significantly decreases the AD risk 1. ApoE is a multifunctional protein that has an important role in modulating plasma lipid and lipoprotein levels as well as inflammatory responses in the brain and periphery 3, 4, 5. Binding of ApoE to low‐density lipoprotein (LDL) receptors in the liver mediates the clearance of chylomicrons and LDL from the bloodstream.…”

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

“…APOE is supposed to be the original gene found to have a genetic linkage with AD (Strittmatter et al 1993). Several years after this discovery, APOE was reported to play an essential role in AD inflammation (Guo et al 2004). Most recently, in 2012, APOE was found to trigger an inflammatory cascade that weakens the bloodbrain barrier (BBB) through an inflammatory molecule known as cyclophilin A (CypA) (Bell et al 2012).…”