Mechanism behind memory impairment caused by LPS neuro-inflammation

Mechanism behind memory impairment caused by LPS neuro-inflammation

07 Fév Mechanism behind memory impairment caused by LPS neuro-inflammation

Alzheimer’s disease (AD) is a progressive neuro-psychiatric disorder which is characterized by the formation of senile plaques (SPs), extracellular deposits of amyloid beta-peptides (Aβ) following intracellular neurofibrillary tangles (NFTs) of the microtubule-associated protein tau. Both cause neuronal degeneration, extensive loss of neurons and synaptic loss which ultimately lead to impaired learning and memory functions. However, neuro-inflammation has been known to play a role in the pathogenesis of AD, as tissue levels of inflammatory mediators including cytokines, chemokines, oxygen free radicals and reactive nitrogen species, are altered.

A systemic inflammation like the one observed in AD patients can be induced by an intraperitoneal injection of lipopolysaccharide (LPS). This injection also induces cognitive impairment in mice. Indeed, researchers observed that upon Intraperitoneal injection of LPS, (250 μg/kg) memory impairment was induced. This was determined using passive avoidance and water maze tests in mice. The repeated injection of LPS (250 μg/kg, 3 or 7 times) resulted in an accumulation of Aβ in the hippocampus and cerebralcortex of mice brains. A substantial increase of apoptotic cells was also found in the hippocampus of LPS treated mice, verifying the relationship between LPS-induced accumulation of Aβ and neuronal cell death. These effects could all be suppressed by an anti-inflammatory agent. However, the underlying mechanisms involved in LPS induced cognitive impairment remain unknown.

To investigate the impact of systemic inflammation on memory impairment and its role in cortical amyloid formation and deposition, researchers induced a systemic inflammation in mice through an intraperitoneal injection of LPS. They then investigated the possible mechanisms of LPS-induced memory impairment, neuro-inflammation and amyloidogenesis in vivo and in vitro using immunohistochemistry, ELISA, behavioural tests and Western blotting.

Following a single injection of LPS, the activities of β and γ-secretase in the cortex and hippocampus increased, whereas, the activity of α-secretase decreased in mice brains. Moreover, LPS treatment increased expression of amyloidogenic proteins APP, BACE and C99 accompanied with the increase of inflammatory proteins iNOS and COX-2 expression. Similar to the in vivo results, in vitro tests showed that the inflammatory stimuli concomitantly increased expression of amyloidogenic proteins and increased the expression of inflammatory proteins in both astrocytes and neuronal cells. These results indicate amyloidogenic pathway could be promoted by neuro-inflammatory stimulation in in vitro and in vivo.

Overall the study showed that systemic inflammatory stimuli elevated amyloidogenesis through activation of β- and γ-secretases accompanied with inhibition of α-secretase which together led to elevated Aβ levels in vivo and in vitro. This co-elevated inflammation and amyloidogenesis resulted in neuronal cell death, and thus memory impairment. The use of an anti-inflammatory agent is however sufficient to inhibit both amylodogenesis and neuro-inflammation which led to recovery effects on the LPS-induced memory impairment. In conclusion, the study suggests that systemic neuro-inflammatory reactions could contribute to the development and/ progression of AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

 

https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-5-37

Syncrosome is an Efficacy Characterization CRO that offers relevant disease models, cutting-edge techniques and a comprehensive background of physiopathology to assist drug discovery companies. Syncrosome uses LPS-rodent for neuro-inflammation.

 

key words: Alzheimer’s disease, preclinical CRO, preclinical study, animal model, animal research, dopaminergic neurons, hippocampus, cerebral cortex, neuroprotection, Alzheimer animal model, LPS, drug, LPS pre-clinical, amyloidogenesis, intracellular neurofibrillary tangles, amyloid beta peptide, senile plaques, neuro-inflammation, pathogenesis, cytokines, chemokines, oxygen free radicals, intraperitoneal injection of lipopolysaccharide

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