Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid ß peptide.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid ß peptide (Aß) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aß have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aß oligomerization. Here, we found that the level of Aß oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aß oligomers. To test this hypothesis, we examined the effect of apoE on Aß oligomer formation. Using both synthetic Aß and a split-luciferase method for monitoring Aß oligomers, we observed that apoE increased the level of Aß oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aß oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aß oligomers in the brain. Higher levels of Aß oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.

Four-dimensional microglia response to anti-Aß treatment in APP/PS1xCX3CR1/GFP mice.

Senile plaques, mainly composed of amyloid-ß (Aß), are a major hallmark of Alzheimer disease (AD), and immunotherapy is a leading therapeutic approach for Aß clearance. Although the ultimate mechanisms for Aß clearance are not well known, characteristic microglia clusters are observed in the surround of senile plaques, and are implicated both in the elimination of Aß as well as the deleterious inflammatory effects observed in AD patients after active immunization. Therefore, analyzing the direct effect of immunotherapy on microglia, using longitudinal in vivo multiphoton microscopy can provide important information regarding the role of microglia in immunotherapy. While microglia were observed to surround senile plaques, topical anti-Aß antibody administration, which led to a reduction in plaque size, directed microglia toward senile plaques, and the overall size of microglia and number of processes were increased. In some cases, we observed clusters of microglia in areas of the brain that did not have detectable amyloid aggregates, but this did not predict the deposition of new plaques in the area within a week of imaging, indicating that microglia react to but do not precipitate amyloid aggregation. The long-term presence of large microglial clusters in the surrounding area of senile plaques suggests that microglia cannot effectively remove Aß unless anti-Aß antibody is administered. All together, these data suggest that although there is a role for microglia in Aß clearance, it requires an intervention like immunotherapy to be effective.