Microglial Activation in Alzheimer Disease: Association with APOE Genotype

Abstract

Microglial cells are considered to play an important role in the pathogenesis of Alzheimer disease. Apart from producing the Alzheimer amyloid precursor (APP) as an acute phase protein, microglial cells seem to be involved in the deposition of its amyloidogenic cleavage product, the amyloid-␤ peptide (A␤). A␤ is bound by apolipoprotein E (APOE) in an isoform-specific manner, and it has been demonstrated that inheritance of the AD susceptibility allele, APOE ⑀4, is associated with increased deposition of A␤ in the cerebral cortex. However, the relationship between APOE ⑀4 gene dose and microglial activation is unknown. Using microglial expression of major histocompatibility complex class II molecules as a marker, we have performed a quantitative genotype-phenotype analysis on microglial activation in frontal and temporal cortices of 20 APOE genotyped AD brains. The number of activated microglia and the tissue area occupied by these cells increased significantly with APOE ⑀4 gene dose. When a model of multiple linear regression was used to compare the relative influence of APOE genotype, sex, disease duration, age at death, diffuse and neuritic plaques as well as neurofibrillary tangles on microglial activation, only APOE genotype was found to have a significant effect. Thus, the APOE gene product represents an important determinant of microglial activity in AD. Since microglial activation by APP has been shown to be modulated by apoE in vitro, a direct role of microglia in AD pathogenesis is conceivable.

Human High Temperature Requirement Serine Protease A1 (HTRA1) Degrades Tau Protein Aggregates

“…Quantitative analysis of neuritic plaques and neurofibrillary tangles was performed using sections from the medial frontal gyrus (46). Briefly, immunophenotypes of AD brains were analyzed quantitatively by determining the number of A␤/tau-positive neuritic plaques and the number of tau-positive neurofibrillary tangles (anti-A␤, 6F/3D, 1:1,000; anti-tau, AT8, 1:2,000).…”

Effects of APOE ε4, age, and HIV on glial metabolites and cognitive deficits

“…Elevated parietal MI is found in patients with AD, 23 and likely reflects greater microglial activation, especially in e41 individuals. 24 Likewise, ApoE4 mice displayed greater and more prolonged increases of cytokines (IL-1b, IL-6, tumor necrosis factor-a) than ApoE2-and ApoE3-expressing mice. 25 The lack of an e41-mediated inflammatory response in the parietal cortex of e41 HIV subjects may reflect microglial dystrophy due to the premature aging.…”

Interferon‐γ protects against the development of structural damage in experimental arthritis by regulating polymorphonuclear neutrophil influx into diseased joints

“…Sections were stained with rat anti-mouse F4/80 (1:50; Serotec, Oxford, UK) or rabbit anti-mouse CXCR2 (1:50; Santa Cruz Biotechnology, Santa Cruz, CA), and antibody binding was detected using the appropriate biotin-conjugated secondary antibody followed by StreptABComplex (Dako). Sections were developed using diaminobenzidine substrate and counterstained with hematoxylin, and the staining index was quantified using the computerbased image analysis system Improvision Density Slicing (Openlab, Coventry, UK) (25,26).…”