Neuronal oxidative damage and dendritic degeneration following activation of CD14-dependent innate immune response in vivo

Dejan Milatovic,Kathleen S Montine,Snjezana Zaja-Milatovic,Thomas J Montine,Feng-Shiun Shie

doi:10.1186/1742-2094-1-20

Abstract

The cause-and-effect relationship between innate immune activation and neurodegeneration has been difficult to prove in complex animal models and patients. Here we review findings from a model of direct innate immune activation via CD14 stimulation using intracerebroventricular injection of lipopolysaccharide. These data show that CD14-dependent innate immune activation in cerebrum leads to the closely linked outcomes of neuronal membrane oxidative damage and dendritic degeneration. Both forms of neuronal damage could be blocked by ibuprofen and alpha-tocopherol, but not naproxen or gamma-tocopherol, at pharmacologically relevant concentrations. This model provides a convenient method to determine effective agents and their appropriate dose ranges for protecting neurons from CD14-activated innate immunity-mediated damage, and can guide drug development for diseases, such as Alzheimer disease, that are thought to derive in part from CD14-activated innate immune response.

Highlights

Activated innate immunity is associated with several degenerative and destructive brain diseases including Alzheimer disease (AD), HIV-associated dementia (HAD), ischemia, head trauma, stroke, cerebral palsy, and axonal degeneration in multiple sclerosis [1]
There are 9 known human plasma membrane-spanning Toll-like receptor (TLR) expressed in many cell types throughout the body that have been discovered in the context of innate immune response to micro-organisms
Our results showed that genetic ablation of one co-receptor (CD14), the required adaptor (MyD88), or one arm of the initial signal cascade each completely blocks an LPS-induced increase in cerebral F4NeuroPs (Table 1)

Summary

Introduction

Activated innate immunity is associated with several degenerative and destructive brain diseases including Alzheimer disease (AD), HIV-associated dementia (HAD), ischemia, head trauma, stroke, cerebral palsy, and axonal degeneration in multiple sclerosis [1]. Neuronal oxidative damage Numerous methods exist to determine free radical-mediated damage to cells While most of these function well in vitro, important limitations arise in living systems where extensive, highly active enzymatic pathways have evolved to metabolize many of the commonly measured products, We first determined the time course of F4-NeuroP accumulation in cerebrum of wt mice exposed to ICV LPS and observed a delayed, transient elevation that peaks at approximately 24 hr after exposure and returns to baseline by 72 hr post exposure [14]. AA: arachidonic acid; AD: Alzheimer disease; AT: α-tocopherol; Aβ: amyloid beta; COX-2: cyclooxygenase 2; DHA: docosohexaenoic acid; EP2: prostaglandin E2 receptor subtype 2; F2-IsoPs: F2-isoprostanes; F4-NeuroPs: F4-neuroprostanes; GT: γ-tocopherol; HAD: HIV-associated dementia; ICV: intracerbroventricular; iNOS: inducible nitric oxide synthase; LPS: lipopolysaccharide; MPO: myeloperoxidase; NSAIDs: nonsteroidal anti-inflammatory drugs; PG: prostaglandin; PGE2: prostaglandin E2; TLR: Toll-like receptor; wt: wild type

Conclusions

Findings

Akira S