Effect of neuroinflammation on cognition and potential mechanisms involved

Abstract

Chronic inflammation in the central nervous system (CNS) is thought to play a role in learning and memory deficits that are prevalent in neurodegenerative diseases such as Alzheimer¿s disease (AD) (Rosi et al. 2005). The association between neuroinflammation and learning and memory deficits were investigated. Below are a summary of the findings of the present work.

Acute peripheral administration of lipopolysaccharide (LPS), a bacteria cell wall proteoglycan, is unable to elicit spatial learning and object recognition deficits when tested 24 hours after administration. This contradicts what was previously reported where a single acute dose of LPS was sufficient to induce a cognitive deficit in rodents.

A spatial learning and object recognition memory deficits were observed in animals dosed with the increasing LPS dose regime. This is the first time that peripheral administration of LPS was shown to be able to elicit an object recognition deficits in rats. During the time of test, animals did not exhibit any sickness behaviour. This strengthens the hypothesis that the cognitive impairment observed were devoid of confounding factors such as sickness behaviour.

The increasing LPS dosing regime was shown to elicit a neuroinflammatory response where elevated tumour necrosis factor a (TNFa) and major histocompatibility complex II (MHCII) were observed in both hippocampus and cortex even after the completion of the treatment. The continuous inflammatory response seen is specific only to the CNS as peripheral system TNFa expression was only shown to be elevated only after the first dose of LPS and returned to the basal level in subsequent doses.

The LPS treatment induced several changes that may serve to explain the cognitive deficits observed. In the hippocampus, an increase in amyloidogenesis, demonstrated by the increase in amyloid precursor protein (APP). Furthermore, LPS treatment may affect glutamatergic transmission, cholinergic innervations and also synaptic plasticity. The alteration of these properties in neural networks may be associated with the cognitive deficits observed and illustrate the role of neuroinflammation in AD.

The effect of the LPS treatment is not limited to an acute effect. When the animals were tested 8 to 12 weeks post LPS treatment, a similar spatial learning deficit. This suggests that there exist a critical window where a delayed cognitive impairment can be observed. This deficit could be due to the alteration in the neurogenesis processes in the dentate gyrus.