Microglial activation induced by factor(s) contained in sera from Alzheimer-related ApoE genotypes

Abstract

Several factors that increase the likelihood of developing Alzheimer's disease (AD) have already been identified. A correct evaluation of these may contribute to a better understanding of the etiology of the disease. The risk of developing AD definitely increases with (a) age, (b) head injuries, (c) family history of AD or Down syndrome, (d) sex (higher prevalence of AD in women), (e) vascular disease, (f) exposure to environmental toxins, (g) infectious processes, or (h) changes in immune function, and recent advances in molecular genetics have suggested that genetic predisposition (i) can be considered one of the most important risk factors in the development of AD. A significant increase in the number of amyloid plaques in AD patients with an apolipoprotein E4 (ApoE) allele has been observed and the results of several genetic studies indicate that the etiology of this neurodegenerative disease is associated with the presence of the allele E4 of ApoE. A potential source of damage in the AD brain is an altered response triggered by microglial activation, which is associated with amyloid plaques. It has become evident that a dysregulation of cytokine release appears within lesions of many types of brain disorders including infection, trauma, stroke, and neurodegenerative diseases. Many studies have shown that microglia secrete both cytokines and cytotoxins and since reactive microglia appears in nearly every type of brain damage, it is likely that their secreted products ultimately help to determine the rate of damaged brain tissue. In this study, in vitro cell cultures were established to investigate the effect of different concentrations of human sera (2.5% and 10%) with specific ApoE genotypes from Alzheimer's and non-Alzheimer's subjects on ameboid and flat microglial cells obtained from neonatal rat hippocampi. Results show that a modulation in the proliferation and activation of microglial cells was obtained and that AD sera, mainly in the ApoE 3/4 and 4/4 genotype contain factor(s) which are able to induce morphological changes, as measured by an increase in the ameboid cell type. In addition, major histocompatibility complex (MHC) class II antigen expression, as measured by flow cytometric analysis, and interleukin-1beta (IL-1beta) release as measured by enzyme linked immunoadsorbent assay (ELISA), in comparison with control groups and lipopolysaccharide (LPS)-treated cells, clearly demonstrate a direct effect of ApoE 3/4 and 4/4 and/or an indirect effect mediated by the release of IL-1beta on microglia activation. These results strongly suggest that primary in vitro microglial cell cultures can be used as a screening model to test human sera as well as the effect of new potential drugs aimed at down-regulating microglia activation.

Microglial activation and amyloid deposition in mild cognitive impairment

“…Against this, we detected increased binding in the anterior and posterior cingulate, relatively small structures compared to our other interrogated ROIs. Finally, evidence exists for multiple factors apart from A␤ that may influence reactivity of microglia within brain, for example ApoE4 status 33 and region-specific differences in the reactivity of microglial populations. 34 We did not perform apolipoprotein E genotyping in our subjects.…”

A pharmacogenomic approach to Alzheimer’s disease

“…The defective PS2 exon 5 (PS2+ genotype) also induces a negative effect in any allelic combination, showing in all cases a poorer therapeutic outcome than the PS2− genotype. In addition, APOE‐related differences in cognitive and non‐cognitive symptoms (40), plasma β‐amyloid levels, serum Apolipoprotein levels (41), microglia activation, IL‐1 production (42) and CSF tau protein levels (43) have been reported, but others did not find any association between APOE‐4 and global cognitive performance or CSF markers (44). Lymphocyte apoptosis in AD also show a genotype‐dependent pattern (Lombardi & Cacabelos, in preparation); and it has also been demonstrated that PS1‐ and PS2‐related factors influence brain atrophy in AD (Cacabelos, unpublished).…”

Immunization for Alzheimer's disease

“…As for other inflammatory compounds, several acute phase reactants, such as apolipoprotein E (ApoE) [Namba et al, 1991;Wisniewski and Frangione, 1992], serum amyloid Pcomponent [Coria et al, 1988;Duong et al, 1989], C-reactive protein [Iwamoto et al, 1994], a1-antichymotrypsin [Abraham et al, 1988], a1-antitrypsin [Gollin et al, 1992], and a2-macroglobulin [Bauer et al, 1991] are associated with plaques and tangles. One of the isoforms of ApoE, ApoE4, is associated with increased risk for AD [Strittmatter et al, 1993] and ApoE enhances microglial expression of various inflammatory molecules [Laskowitz et al, 1997[Laskowitz et al, , 1998 in an isoform-dependent manner [Barger and Harmon, 1997;Lombardi et al, 1998]. Not only is there a complex interaction/regulation between these compounds, many of them have been shown to act specifically with Ab/APP and/or its fragments.…”