MICROGLIAL ACTIVATION IN ALZHEIMER-DISEASE - ASSOCIATION WITH APOE GENOTYPE

Microglial cells are considered to play an important role in the patho genesis of Alzheimer disease. Apart from producing the Alzheimer amylo id precursor (APP) as an acute phase protein, microglial cells seem to be involved in the deposition of its amyloidogenic cleavage product, the amyloid-beta peptide (A beta), A beta is bound by apolipoprotein E (APOE) in an isoform-specific manner, and it has been demonstrated th at inheritance of the AD susceptibility allele, APOE epsilon 4, is ass ociated with increased deposition of A beta in the cerebral cortex. Ho wever, the relationship between APOE epsilon 4 gene dose and microglia l activation is unknown. Using microglial expression of major histocom patibility 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 numb er of activated microglia and the tissue area occupied by these cells increased significantly with APOE epsilon 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 ne uritic plaques as well as neurofibrillary tangles on microglial activa tion, only APOE genotype was found to have a significant effect. Thus, the APOE gene product represents an important determinant of microgli al activity in AD. Since microglial activation by APP has been shown t o be modulated by apoE in vitro, a direct role of microglia in AD path ogenesis is conceivable.