Inflammation as a therapeutic target for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterised by impairment of memory and learning. The impairment is caused by neuronal death which originates in the parts of the brain that execute memory functions: the entorhinal cortex and hippocampus. The neuronal death is believed to be caused by the amyloid- (A) peptide which is prone to oligomerisation and aggregation into insoluble amyloid plaques (AP). The levels of soluble A and the number of AP:s are increased in the AD brain which is attributed to increased production and impaired clearance of A. Another hallmark of AD, after neuronal death and the increased presence of A, is inflammation in the form of activated microglia and increased levels of inflammatory proteins in the brain. Inflammation in the CNS has been shown to increase the production of A and to impair, and even kill, neurons.

On the other hand, inflammation has been shown to increase the removal of pathogens, such as A, from the brain by increasing the phagocytic acticity of microglia. Inflammation is also associated with an increased secretion of neurotrophic factors that can protect neurons. Somehow this clearance of A is impaired in AD and the levels of neurotrophic factors are decreased. The work on this thesis has been focused on the inflammatory component of AD and how it can be modulated into performing activities that are beneficial for neurons without evoking the harmful activities of inflammation. For this purpose a human microglial cell line, CHME3, was characterized with regard to interaction with A and inflammatory responses. The CHME3 microglial cell line was used as a model of inflammation in the human brain. In this model, we tested the ability of the neuropeptide -MSH to inhibit inflammation induced by A1-40 and cytokines, and found that -MSH, on the contrary, increased secretion of the inflammatory cytokine interleukin (IL)-6. -MSH was also found to protect human neuronal cells against necrotic stress. The possibility of stimulating microglia into phagocytosis of A1-42 and the concurrent responses was also investigated.

We found that the omega-3 fatty acid DHA and the adjuvant protollin had a stimulatory effect on phagocytosis of A1-42. DHA also had an inhibitory effect on the secretion of several cytokines. Microglia that were phagocytic of A1-42 displayed increased expression of several inflammatory markers compared to non-phagocytic cells. Thus, inducible nitric oxide synthase (iNOS) was expressed to a larger extent on phagocytic cells. Treament with DHA abolished this imbalance in iNOS expression, indicating a less harmful phenotype of phagocytic cells upon treatment with DHA. Furthermore, inflammation in the form of IFN stimulated phagocytosis of A1-42 while decreasing the secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) and inducing microglial cell death. A1-42 was also found to decrease the secretion of BDNF. The effect of omega-3 supplement on the levels of A1-42, tau and inflammatory markers in the cerebrospinal fluid and plasma of AD-patients was investigated in an intervention study.

There were no detectable differences in any of the markers after 6 months of treatment with omega-3 compared with placebo control. However, at base line, a significant positive correlation between the soluble interleukin (IL)-1 receptor type II was observed. The major finding in this thesis is the reduction in BDNF induced by A1-42, and the AD-related cytokine IFN, suggesting a new pathogenic mechanism in AD. Other important findings are the beneficial effect of DHA on microglial activities, which support the use of omega-3 supplements for treatment of AD. However, the results from the intervention study did not provide additional support for the use of omega-3, but suggest the importance of early intervention. -MSH was found to promote neuronal survival suggesting a potential role for this peptide and its receptors for the treatment of neurodegenerative disorders.