EFFECTS OF ALZHEIMER’S DISEASE GENETIC RISK FACTOR APOE4 ON THE NORMAL BRAIN

Abstract

Over 70 million Americans inherit the strongest genetic risk factor for Alzheimer’s disease (AD), the E4 allele for apolipoprotein E (APOE4), but have few strategies to reduce their risk. To identify markers associated with APOE genotype, we have examined APOE4 knock-in mice, which display deficits in spatial learning and dendritic spine density in the medial entorhinal cortex, an area of the brain affected early in AD. Here, we report new APOE4-associated phenotypes in mice: increased levels of post-translational modifications (PTMs) of APOE via O-linked glycosylation and sialylation, increased ATP-Binding Cassette Transporter A1 (ABCA1) levels, increased Glucose Transporter 1 (GLUT1) levels, and decreased medial temporal lobe volume.

We examined these phenotypes after putative AD preventive drug treatments to investigate whether APOE4-associated phenotypes are modifiable. Epidemiology studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) reduce AD risk, particularly in APOE4-carriers. Thus, we treated APOE4 mice with NSAID ibuprofen, which acts as both a COX-2 inhibitor and PPAR-γ agonist. We also treated independent cohorts of animals with a selective COX-2 inhibitor (celecoxib) and a PPAR-γ agonist (pioglitazone). We found that ibuprofen fully mitigated, while celecoxib and pioglitazone partially mitigated, the APOE4-associated phenotypes, suggesting that both targets of ibuprofen are important for its effects.

To identify the mechanism by which APOE affects dendritic spine density and cognition, we also studied the APOE receptor Very Low Density Lipoprotein Receptor, VLDLR. We discovered that VLDLR is found at the synapse, and dendritic spine number was dependent on VLDLR expression. Additionally, VLDLR knockdown differentially regulated levels of glutamate receptor subunits. We further found that VLDLR interacts with the Ras signaling pathway, which is involved in spinogenesis and neurodegeneration, to exert its effects at the synapse.

Importantly, these findings have relevance in human APOE4-carriers. As seen in mice, alterations in PTMs of APOE and medial entorhinal cortex volume were observed in human APOE4 carriers. Functionally, APOE4 risk also contributed to performance on a memory task. These findings demonstrate that APOE4 mice are a powerful model to identify measures of APOE-associated AD risk, and demonstrate a mechanism by which ibuprofen may reduce risk of AD in APOE4 carriers.