CIS-ACTING HUMAN APOE TISSUE EXPRESSION ELEMENT IS ASSOCIATED WITH HUMAN PATTERN OF INTRANEURONAL APOE IN TRANSGENIC MICE

Apolipoprotein E polymorphic variants (ApoE-epsilon 2, epsilon 3, and epsilon 4) are associated with the age of onset distribution and risk of Alzheimer disease. The question of whether ApoE is expressed at a c omparatively low level in human neurons compared to astrocytes, or whe ther ApoE enters neuronal cytoplasm via altered endosomal metabolism i s important to understanding potential pathogenic roles for ApoE as a susceptibility gene in Alzheimer disease. ApoE deficient (''knock-out' ') mice received large human genomic DNA fragment transgenes for each of the three common apoE alleles. All transgenic mice demonstrated gli al/astrocytic (normal rodent pattern), as well as cortical intraneuron al ApoE immunoreactivity with all three human isoforms and at multiple ApoE human allele doses (Xu et al. (32)). To test whether ApoE intran euronal immunoreactivity was due to ApoE gene sequences between mouse and human, we examined another set of mice constructed using targeted replacement so that the human ApoE gene was placed under mouse gene pr omoters. Current analyses show that targeted replacement recombinant m ice show normal rodent glial expression pattern, but no ApoE neuronal immunoreactivity through six months of age compared to large human gen omic DNA fragment transgenic mice, which show neuronal content of ApoE throughout adult life. We conclude that cis-acting DNA sequences, rat her than the specific sequence of the ApoE gene, may be responsible fo r low levels of transcription activity in cortical neurons. (C) 1998 E lsevier Science Inc.