The role of immune activation in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the most common cause of progressive dementia and a neurodegenerative disorder, which despite scientific progress in recent years is still a disease of unknown etiology. One pathological hallmark of AD is the presence of neuritic plaques in the cortical gray matter. These extracellular depositions are mainly composed of aggregated amyloid-beta (A?) peptides and are surrounded by dystrophic neurites and glial cells. The A? peptide is derived through changes in the processing of the amyloid-beta precursor protein and according to the ‘amyloid cascade hypothesis’ these changes are central to the disease process. A? is a 4 kDa peptide of 39-43 amino acids and studies with synthetic A? show that it can act as a potent and direct neurotoxic agent. There is however an increasing amount of evidence that A? can be indirect neurotoxic by activating surrounding glial cells. Neuritic plaques, but not diffuse plaques, are reported to be surrounded by microglia. Since microglia are able to produce cytokines as well as chemotactic and neurotoxic factors a lot of research has focused on the ability of A? to induce these events in microglia. The scope of this thesis is to question the role of these surrounding glial cells, microglia and astrocytes, in the inflammatory process and the continuation of this process. The results presented in chapter 2 show the effect of A?(25-35) on the binding of A?(1-42) to macrophages and the consequent superoxide anion production. A?(25-35) markedly enhanced the effect of A?(1-42). Chapter 3 shows that both ERK 1/2 and p38 MAPK signal transduction pathways as well as PKC are involved in the amyloid-?-stimulated superoxide anion production in macrophages. In contrast, only ERK 1/2 MAPK seems to be involved in TNF-? production, questioning the connection between PKC and ERK 1/2 activation. Chapter 4 shows that A? is able to induce TNF-? and superoxide anion production in macrophages and that astrocytes do not produce these inflammatory mediators. In cocultures however a decreased production of these putative neurotoxins was seen, probably due to the binding of A? to the astrocytes. A? is able to induce NF-?B activation in astrocytes. However, due to the already high NF-?B activity in macrophages, an additional effect of A? could not be detected. Chapter 5 shows the ability of A?(1-42) to stimulate the production, and expression of MIP-1? and MIP-1? in macrophages and MCP-1 in astrocytes and in cocultures their of. In chapter 6 the effectiveness of these CC-chemokines to attract monocytes was investigated. Using neutralizing antibodies it was shown that A?-stimulated macrophages produce MIP-1?, MIP-1? and MCP-1 in such amounts that they attract monocytes.