Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice

Zhao J, Bi W, Xiao S, Lan X, Cheng X, Zhang J, Lu D, Wei W, Wang Y, Li H, Fu Y, and Zhu L. (2019). Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Scientific Reports, 9

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and memory loss. There is no agreed upon cause of AD, but many factors are associated with its risk including the accumulation of toxic proteins such as β-amyloid (Aβ) and hyperphosphorylated tau (p-tau), poor diet, history of mental illness, poor cholesterol transport, and reduced plasmalogen levels. Zhau et al characterized the widely used lipopolysaccharide (LPS) model, demonstrating that it provides an accurate model of AD and disease progression through producing both the behavioural and pathological manifestations of AD, including cognitive impairment, increased anxiety, decreased locomotion, weight loss, general behavioral depression, neuronal loss, microglial activation, and inflammation.

To determine what areas of cognition were affected in the LPS-treated mice, the Morris water maze (MWM) was used to study spatial learning and memory. In the MWM test, the control mice learned to find the platform in the pool within 10-15 seconds, but the mice that received LPS took twice as long (24-31 seconds), indicating clear memory deficit in these mice. To evaluate the motor coordination of the mice, the climbing pole test was employed. A point system was used to compare the time it took control mice to climb down a 60cm pole compared to the LPS mice. The latter were found to have a significantly lower score indicating that the mice had poorer coordination and moved slower.

As neuronal loss and microglial activation are found in people with AD, both were examined in the LPS model. IBA-1, a marker of microglia, and MAP-2, found in the axons and dendrites of neurons, were observed in the hippocampus. The mice who received LPS showed 15.7-18.8% of MAP2-positive cells compared to ~80% in the hippocampus of the control mice, indicating greater neuronal loss. As well, the LPS-induced animals showed ~65% IBA1-positive cells compared to ~10% seen in the controls, which would suggest that the LPS treatment has induced microglial activation.

To observe any proinflammatory reaction caused by the LPS administration, cytokines including TNF-α, IL-1β, PGE2 and NO were measured in the serum and brain homogenates of the mice. It was found that TNF-α and IL-1β were higher in the LPS-induced mice compared to the control group, indicating that LPS resulted in inflammation and release of proinflammatory cytokines. As well, PGE2 and NO were found to be increased in the LPS-treated animals, also supporting that these mice have an inflammatory reaction to LPS. Finally, Aβ expression was greater in the hippocampus of the mice that received LPS than the control group.

The largest challenges with models of AD are that there is no model that demonstrates every hallmark of the disease, the effects are sudden and not progressive, or the model is caused by an overexpression of a toxic protein that does not occur in the human manifestation of AD. Most of the research done in AD has looked at overexpressing Aβ and/or p-tau although results are inconsistent and have shown poor translatability to the clinic. LPS has been used to study neurodegenerative diseases and cognitive dysfunction because the pathology that manifests after LPS administration is similar to what is seen in patients with these diseases, such as AD. A key factor in the development of AD is neuroinflammation, which is often lacking in typical animal models for AD. Many reports have shown that LPS causes neuroinflammation, microglial activation, neuronal cell loss, amyloid production, and memory deficits, consistent with AD pathology. In addition, other studies have associated a reduction in plasmalogen levels with LPS administration, further implicating this method as a more appropriate model for the study of AD.