Inflammation & LPS

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Inflammation and LPS (lipopolysaccharides)

Inflammation plays an important role in the pathology of AD. Inflammation can be beneficial, but when left unchecked, becomes detrimental. “Lipopolysaccharides (LPS), also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals” (Wikipedia). The Wikipedia page also reports that humans are much more sensitive to LPS than other animals. Lipopolysaccharides are known to induce inflammatory responses and are often used to induce central nervous system inflammation in mouse studies.

BACKGROUND ON INFLAMMATION IN AD

- Inflammation in Alzheimer Disease—A Brief Review of the Basic Science and Clinical Literature (2011, full text)


- Lipopolysaccharide-Induced Inflammation Exacerbates Tau Pathology by a Cyclin-Dependent Kinase 5-Mediated Pathway in a Transgenic Model of Alzheimer's Disease (2005, full text)

“Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidβ-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of central nervous system inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.”


- Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1β and IL-6 (2011, full text)

LPS can act directly at the brain endothelium to induce CNS inflammatory gene transcription.

It is emerging that systemic inflammation has significant deleterious effects on the progression of neurodegenerative disease, and understanding the mechanisms by which this occurs is an important priority. It has generally been assumed that cytokines induced by systemic inflammatory stimulation have a key role in the central nervous system effects of systemic inflammation. While systemic cytokines certainly can achieve a number of central nervous system effects, the data presented here indicate that these cytokine responses are not essential for the effects on behaviour, central nervous system inflammation, and cell death shown here. Understanding how systemic inflammatory events impact on progression of neurodegenerative disease will have implications for treatment of these patients.”

Evidence

Epidemiological studies.

- High throughput DNA sequencing to detect differences in the subgingival plaque microbiome in elderly subjects with and without dementia. (2012, full text)

"Sparks Stein et al. [13] found elevated levels of antibodies to Prevotella intermedia and Fusobacterium nucleatum in the blood of subjects who later developed AD. These investigators also found that subjects with Mild Cognitive Impairment (MCI), unlike AD subjects, had no differences in P. intermedia and F. nucleatum compared to normal subjects, but had reduced levels of antibodies to several other oral bacteria.

There appears to be a consistent difference in the levels of Fusobacteriaceae, and perhaps Prevotella, in [subgingival] samples from patients who do or do not have dementia, which should be studied in more detail."


- Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue. (2013, PubMed ID:23666172) Note small study group size.

“This study confirms that LPS from periodontal bacteria can access the AD brain during life as labeling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology.”


CHD studies.

- Association of serum anti-periodontal pathogen antibody with ischemic stroke. (2012, PubMed ID:23207319) "Our results suggest that anti-Pg antibody is associated with atrial fibrillation and that anti-Pi antibody is associated with carotid artery atherosclerosis. In addition, anti-Pi antibody may be associated with atherothrombotic stroke through its association with carotid artery atherosclerosis. Thus, periodontitis may lead to serious systemic diseases." (Pi is Prevotella intermedia, associated with periodontal disease).


- Prediagnostic plasma antibody levels to periodontopathic bacteria and risk of coronary heart disease. (2012, PubMed ID:22878796) "For subjects aged 56-69 years, the high tertile level (> 414.1 U/mL) of P. intermedia was associated with higher risk of CHD (OR = 2.65; 95% CI = 1.18-5.94) in a dose-response fashion (P for trend = 0.007). The possible role of periodontopathic bacteria as a risk factor for CHD incidence was suggested by the results of this study by the elevated antibody level to these bacteria with the increased risk of CHD."


Animal studies.

- Neuro-Inflammation Induced By Lipopolysaccharide Causes Cognitive Impairment Through Enhancement Of Beta-Amyloid Generation (full text)

Proposed mechanism(s)

LPS-based systemic inflammation triggered by gut dysbiosis, as a factor in AD. (SusanJ’s speculation)

1) Research in rheumatoid arthritis show the role of gut dysbiosis in systemic inflammation.

- Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis (2008, full text)

“In our cohort, we found the microbiota of many subjects to be defined by a single taxon—P. copri—which was associated with the majority of untreated, new-onset rheumatoid arthritis (NORA) patients. P. copri was also detected in a minority of healthy subjects in cohorts from the Human Microbiome Project (Human Microbiome Project Consortium, 2012), the European MetaHIT project (Qin et al., 2010), and our study. Surprisingly, the prevalence of P. copri in chronic rheumatoid arthritis (CRA) patients, all of whom had been treated and exhibited reduced disease activity, was similar to that observed in the healthy subjects. One hypothesis is that the Prevotella-defined microbiota fail to thrive when there is less inflammation, perhaps due to a lack of inflammation-derived terminal electron acceptors, as seen for E. coli in inflammatory bowel disease (Winter et al., 2013). Alternatively, the gut microbiota changes observed in newly diagnosed RA patients may be the consequence of a unique, NORA-specific systemic inflammatory response. While DAS28 scores were slightly lower in CRA and PsA patients (Table 1), the most remarkable difference was in levels of C-reactive protein (CRP). This raises the question of whether CRP itself may have microbial modulating properties. CRP is characteristically high in early and flaring RA, but not in other autoimmune diseases (e.g., systemic lupus erythematous, scleroderma, and PsA). A member of the pentraxin protein family, CRP was first identified in the plasma of patients with Streptococcus pneumoniae infection (Tillett and Francis, 1930). [[Further, the primary bacterial ligand for CRP is phosphocholine, a component of multiple bacterial cell-wall components, including lipopolysaccharides (LPS). CRP binding to bacterial phosphocholine activates the complement system and enhances phagocytosis by macrophages.]] Whether or not CRP itself represents a specific response to the presence of P. copri in NORA is an area of future investigation. Interestingly, Prevotella-dominated healthy omnivore individuals were recently reported to have increased basal levels of serum TMAO (trimethylamine N-oxide), a product of inflammation linked to atherogenesis, compared to Bacteroides-dominated healthy individuals (Koeth et al., 2013). While TMAO could be derived from increased consumption of meat (Koeth et al., 2013), Prevotella has been previously associated with a dearth of meat in the diet (Wu et al., 2011). Additional studies are needed to determine if prevalence of P. copri in the microbiota is associated with changes in specific metabolites.

Another key feature of the P. copri-dominated microbiome is a community shift away from Bacteroides, Group XIV Clostridia, Blautia, and Lachnospiraceae clades, previously reported to be associated with an anti-inflammatory state and regulatory T-cell (Treg) production (Atarashi et al., 2011; Round et al., 2011). This could account, in part, for the observed differences in susceptibility to inflammation (Tao et al., 2011). Further characterization of changes in the host immune system associated with a Prevotella-dominated microbiota should provide deeper insight into whether expansion of P. copri contributes causally to the development of autoimmunity in early onset RA.”


2) Systemic inflammation is typically marked by an increase in CRP and other inflammatory cytokines, which affect the permeability of the blood-brain barrier.

- Astrocyte–endothelial interactions at the blood–brain barrier (2006, full text) “In animal models of Alzheimer's disease, amyloid- (A) accumulation is often first seen in the neighbourhood of blood vessels, with toxicity on endothelium and astrocytes observed before significant neuronal loss1; disturbances of CNS homeostasis as a result of barrier deficiencies could contribute to and exacerbate the later neuropathology100... Lipopolysaccharide (LPS), formed in infections, leads to the release from microglia of tumour necrosis factor- (TNF), IL-1 and reactive oxygen species (including O2-), all of which have the ability to open the BBB (3).”


- Significance of Cerebrospinal Fluid C-reactive Protein Level in Pyogenic and Non-pyogenic Meningitis in Adults (2010, full text)

Today, C-reactive protein (CRP) is one of the most widely used inflammatory markers in the emergency department to distinguish bacterial from non-bacterial infections.

Gojan Rajs et al14 reported from their study that CSF CRP levels are higher in Gram-negative pyogenic meningitis compared to Gram-positive pyogenic meningitis. Similar findings were seen in our study. However, a majority of cases in our study were due to Gram-positive bacteria. This suggests that infection with Gram-negative bacteria enhances permeability of CRP through the blood brain barrier. It is possible that these findings reflect the ability of the endotoxin lipopolysaccharide-S, present in the Gram-negative bacteria, to affect the permeability of blood brain barrier. Nitric Oxide (NO) may be involved in this mechanism because its concentration in CSF is higher in Gram-negative meningitis as observed in other studies. This possibility is supported by the higher potency of Gram-negative bacteria to promote macrophage NO production, the enhanced production of NO in the CSF of pyogenic meningitis, and the role of NO in the permeability changes of the blood brain barrier in lipopolysaccharide-S induced experimental meningitis.”


3) Once LPS crosses the blood-brain barrier, it triggers neuroinflammation, which increases beta-Amyloid.

- Inflammatory response is increased in the presence of LPS, and the animal study cited above showed it causes an increase in beta-Amyloid production in the cortex and hippocampus. The authors note, “The way LPS induces amyloidogenesis is not clear.”


- The LPS receptor (CD14) links innate immunity with Alzheimer’s disease (2003, full text) The innate immune system has been shown to be activated and interact with beta-Amyloid fibrils. The hypothesis is that beta-Amyloid is biophysically similar to pathogen-associated microbial patterns.

Related SNPs

TBD.


APOE4 effects


APOE is an important component of innate immunity, but APOE4 shows higher inflammatory activity than other isoforms.

- Cross-Talk between Apolipoprotein E and Cytokines (2011, full text)

“The distribution of lipids among different body compartments occurs by means of different lipoprotein particles in the blood circulation [21]. Host responses to infections involve changes in lipid levels and lipid metabolism in the plasma. These plasma lipid changes might be mediated by three cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, which induce elevated levels of triglycerides and VLDL [22], decreased levels of cholesterol, HDL and LDL [23, 24] or increased levels of cholesterol in the serum [25], depending on the nature of the infectious agents.

Lipoproteins and lipids present in the serum may contribute to the host innate immunity against pathogens [26]. Studies using apoE deficient mice confirmed the role of apoE in host susceptibility to endotoxemia and Klebsiella pneumoniae infection [27], while transgenic (Tg) mice expressing human APOEε3 and APOEε4 genes revealed an isoform-specific effect of apoE on the proinflammatory response to lipopolysaccharide (LPS) [28]. Infection of apoE knockout (KO) mice with Listeria monocytogenes or Klebsiella pneumoniae leads to an increased susceptibility to death as well as increased serum levels of TNF-α as compared with wild-type (WT) mice [29, 30]. Binding of bacterial endotoxin to either HDL, LDL, or VLDL results in a redirection of endotoxin uptake from Kupffer cells to parenchymal hepatocytes where the endotoxin is deactivated [30]. ApoE facilitated sepsis-induced mortality in a dose-dependent manner and increased natural killer T-(NKT)-cell proliferation in the spleen [31]. ApoE deficient mice were markedly more susceptible to tuberculosis, evidenced by 100% mortality within 4 weeks of infection with tuberculosis [32]...

ApoE suppressed inflammation through VLDLR or apoER2 in macrophages by converting proinflammatory M1 to the antiinflammatory M2 phenotype [42]. Exogenous apoE suppressed LPS and polyinosine-polycytidylic acid (PIC, a double-stranded RNA that serves as a viral mimetic and a Toll-like receptor (TLR)3 agonist) induced secretion of IL-6, IL-1β and TNF-α by RAW 264.7 cells via repressing TLR-agonist-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun. ApoE peptide (141–155)2 inhibits LPS- and PIC-induced macrophage inflammatory responses in a similar manner [43]. ApoE also reduces inflammatory signaling in astrocytes and microglia in response to proinflammatory stimuli [44, 45]...”

In apoE4 versus apoE3 macrophage cell line cells higher levels of proinflammatory cytokines including TNF-α appeared evident followed by LPS stimulation [83].


- Apolipoprotein E4 Impairs Macrophage Efferocytosis and Potentiates Apoptosis by Accelerating Endoplasmic Reticulum Stress (2012, full text)

“Increased cell death was also observed in APOE4 macrophages when stimulated with LPS or oxidized LDL...these results showed that apoE4 expression causes macrophage dysfunction and promotes apoptosis via ER stress induction. The reduction of ER stress in macrophages may be a viable option to reduce inflammation and inflammation-related metabolic disorders associated with the apoE4 polymorphism.”


- APOE genotype alters glial activation and loss of synaptic markers in mice (2013, full text)

“APOE4 mice displayed increased glial activation in response to intracerebroventricular lipopolysaccharide (LPS) compared to APOE2 and APOE3 mice by several measures. There were higher levels of microglia/macrophage, astrocytes, and invading T-cells after LPS injection in APOE4 mice. APOE4 mice also displayed greater and more prolonged increases of cytokines (IL-1β, IL-6, TNF-α) than APOE2 and APOE3 mice. We found that APOE4 mice had greater synaptic protein loss after LPS injection, as measured by three markers: PSD-95, drebin, and synaptophysin. In all assays, APOE knock-out mice responded similar to APOE4 mice, suggesting that the apoE4 protein may lack anti-inflammatory characteristics of apoE2 and apoE3. Together, these findings demonstrate that APOE4 predisposes to inflammation, which could contribute to its association with Alzheimer's disease and other disorders.”

Theoretical concerns

TBD


Treatment

- Resveratrol in Mouse models

Consuming a Diet Supplemented with Resveratrol Reduced Infection-Related Neuroinflammation and Deficits in Working Memory in Aged Mice (2009, full text) "As anticipated, deficits in locomotor activity and spatial working memory indicated aged mice are more sensitive to LPS compared to adults. More importantly, the LPS-induced deficits in aged animals were mitigated by dietary supplementation of resveratrol. In addition, resveratrol consumption reduced LPS-induced interleukin-1β (IL-1β) in plasma and the IL-1β mRNA in the hippocampus of aged mice. Finally, pretreatment of BV-2 microglial cells with resveratrol potently inhibited LPS-induced IL-1β production. "


Summary

Bottom line, keep inflammation under control. Watch sCRP levels, practice healthy dental habits, work on gut health and treat infections.