Neuro-Inflammation Induced By Lipopolysaccharide Causes Cognitive Impairment Through Enhancement Of Beta-Amyloid Generation

Jae Woong Lee; Yong Kyung Lee; Dong Yeon Yuk; Dong Young Choi; Sang Bae Ban; Ki Wan Oh; Jin Tae Hong

Disclosures

J Neuroinflammation 

In This Article

Abstract and Background

Abstract

Background: Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Aβ) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD.
Methods: In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting.
Results: Intraperitoneal injection of LPS, (250 µg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 µg/kg, 3 or 7 times) resulted in an accumulation of Aβ1-42 in the hippocampus and cerebralcortex of mice brains through increased β- and γ-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Aβ1-42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5-50 µM) also suppressed LPS (1 µg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro.
Conclusion: This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

Background

Alzheimer's disease (AD) is a progressive neuro-psychiatric disorder. The major neuropathological hallmarks of AD are the formation of senile plaques (SPs) following neurofibrillary tangles (NFTs) which cause neuronal degeneration and synaptic loss. SPs are extracellular deposits of fibrillar and amorphous aggregates of amyloid beta-peptide (Aβ) whereas NFTs are intracellular fibrillar aggregates of the microtubule-associated protein tau that exhibit hyperphosphorylation. The formation of SPs and NFTs in brain regions such as the entorhinal cortex, hippocampus, basal forebrain and amygdala impaired learning and memory functions.[1] AD brains also exhibit a number of pathological abnormalities, including a profound loss of synapses, reactive gliosis, and inflammatory processes.[2]

The brain has an endogenous immune system that is coordinated by immunocompetent cells such as microglia. The brain is also vulnerable to constitutive defense responses, such as inflammation.[3,4]. The inflammation associated with the brain, neuro-inflammation, differs from that found in the periphery. Although edema and neutrophil invasion, typical features of inflammation, is not seen in the AD brain, tissue levels of inflammatory mediators including cytokines, chemokines, oxygen free radicals and reactive nitrogen species, are altered.[5,6]

Numerous reports have indicated that neuro-inflammatory process contributes to the pathogenesis of AD. Study performed in transgenic animals suggest that neuro-inflammation plays an important role in the process of cerebral amyloid deposition.[7] It has been shown that inflammatory cytokines such as Interleukin (IL)-1β, IL-6, Tumor necrosis factor-αgTNF-α) or Transforming growth factor-β (TGF-β) can augment APP expression[8,9] and Aβ formation.[10] It was also reported that cytokines are able to transcriptionally upregulate β-secretase mRNA, protein and enzymatic activity.[11] β-secretase is a key rate-limiting enzyme that initiates Aβ formation.[12] Without β-secretase, Aβ synthesis is either abolished or considerably reduced.[13] Moreover, McGeer and Rogers proposed possible therapeutic effects of anti-inflammatory agents on the patients with AD.[14] Inflammatory mediators present in AD lesions are thought to stimulate underlying key events of the pathological cascade that result in increased Aβ production with recruitment and activation of microglial cells.[15]

Many persons with AD die with systemic inflammation such as a lung or bladder infection. The systemic inflammation will lead to the generation of circulating cytokines, which will have in turn an impact on the central nervous system.[16] Furthermore, it was also reported that intraperitoneal injection of lipopolysaccharide (LPS) induces cognitive impairment in mice.[17,18] However, underlying mechanisms involved in LPS induced cognitive impairment are not known. To investigate the impact of systemic inflammation on memory impairment and its role in cortical amyloid formation and deposition, mice were intraperitoneally injected with LPS to generate systemic inflammation, and then investigated for the possible mechanisms of LPS-induced memory impairment and amyloidogenesis in vivo and in vitro.

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