IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

Abstract

A hallmark of immunopathology associated with Alzheimer’s disease is the presence of activated microglia (MG) surrounding senile plaque deposition of β-amyloid (Aβ) peptides. Aβ peptides are believed to be potent activators of MG, which leads to Alzheimer’s disease pathology, but the role of MG subtypes in Aβ clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Aβ1–42 (o-Aβ1–42). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Aβ-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Aβ clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of 125I-labeled o-Aβ1–42 compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Aβ1–42 in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Aβ1–42, because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Aβ1–42 were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Aβ-overproducing brain. Thus, selective o-Aβ1–42 clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer’s disease.

CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models

“…In support of this possibility, TNF␣ mRNA levels were selectively down-regulated in CX3CR1 deficient APPPS1 animals, and TNF␣ has been shown to directly reduce microglial expression of A␤-degrading enzymes such as insulin-degrading enzyme and neprilysin. 51,52 Furthermore, IL1␤ mRNA levels were significantly increased in a gene dose-dependent manner in the CX3CR1-deficient APPPS1 animals, and previous studies demonstrated that IL1␤ overexpression enhances A␤ clearance. 9,53 Finally, mRNA levels of MCP-1, which promotes microglia-mediated A␤ oligomerization, 54 was reduced in CX3CR1-deficient APPPS1 animals and thus could lead to reduced A␤ oligomerization/ deposition.…”

“…48 Within the AD brain, there is a chronic activation of microglia associated with inflammatory cytokines including TNF␣ that can substantially block of ability of the microglia to remove 47,49,50 or degrade A␤. 51,52 Recent studies demonstrated that overexpression of IL1␤, an inflammatory cytokine leads to reduced A␤ pathology in mouse models of AD. 9,53 One partial explanation for our results is that CX3CR1 deficiency alters the microglial activation status and enhances A␤ clearance.…”

Norepinephrine Promotes Microglia to Uptake and Degrade Amyloid β Peptide through Upregulation of Mouse Formyl Peptide Receptor 2 and Induction of Insulin-Degrading Enzyme

“…In AD mouse models, the expression levels of neprilysin and IDE in microglia were decreased in 14-month-old mice (Hickman et al, 2008). Recent studies demonstrated that IDE expression and activity were complexly regulated by various factors, including aging, Apo E, cytokines, and vitamin E (Eckman and Eckman, 2005;Jiang et al, 2008;Shimizu et al, 2008;Nishida et al, 2009). Therefore, the upregulation of IDE represents a promising strategy for therapy and prevention for AD.…”

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

“…A previous study found that peripheral mononuclear cells from AD patients showed reduced IL-4 production upon stimulation [107]. In vitro, IL-4 induces the microglial clearance of Ab via promoting the expression of CD36 and Ab-degrading enzymes (neprilysin and insulin-degrading enzyme) [108]. Moreover, in vivo treatment with IL-4 reduces the accumulation of Ab and alleviates the cognitive impairments in AD animal models [109].…”