Different versions of APOE protein have varying effect on microglia in Alzheimer's disease

Alzheimer's disease is the most common cause of dementia in the UK, affecting 1 in 14 people over the age of 65. Alzheimer's is characterised pathologically by a buildup of proteins in the form of amyloid plaques and tau tangles.

The apolipoprotein E (APOE) gene is a major genetic risk factor for Alzheimer's disease. There are three different versions of the APOE protein: APOE2, APOE3, and APOE4. While APOE4 increases the risk of developing Alzheimer's, APOE2 is associated with a lower risk. However, how these isoforms lead to strikingly different risk profiles is poorly understood.

In this study, researchers looked at APOE in microglia, the brain's immune cells known to play a role in Alzheimer's disease. As the three versions of APOE are evolutionarily unique to humans, they can't be directly studied in a mouse brain, posing a challenge to studying them in a laboratory setting.

To overcome this, researchers developed a human "xenotransplantation model." This is where human microglia were grown from stem cells, manipulated to express different APOE versions, then transplanted into the brains of mice that had developed a buildup of amyloid plaques. The microglia were then isolated and analysed for their gene expression (using a technique called transcriptomics) and for their chromatin accessibility (how accessible the DNA is for genes to be expressed).

The researchers uncovered widespread changes to the transcriptomic and chromatin landscape of microglia, dependent on the APOE isoform expressed. The largest differences were observed when comparing the APOE2 and APOE4 microglia.

In APOE4 microglia, researchers saw an increase in the production of cytokines, signalling molecules involved in immune regulation. They also observed diminished capacity for the microglia to migrate and shift into protective states. Furthermore, the microglia became less effective in phagocytosis, a process by which they digest and clear up particles such as debris and pathogens.

Conversely, APOE2 microglia showed increased expression of various genes that increase microglia proliferation and migration, and a decreased inflammatory immune response. Additionally, APOE2 microglia showed increased DNA-binding of the vitamin D receptor. Low levels of vitamin D have been associated with a higher incidence of Alzheimer's.

The study highlights that microglia responses to amyloid pathology differ significantly across APOE versions. This finding underscores that considering the interplay between genetic risk factors and microglial states is critical in disease progression. The study also highlights the potential role of the vitamin D receptor, providing new avenues for therapeutic exploration.

Dr Sarah Marzi, Senior Lecturer in Neuroscience at King's College London and lead author of the study, said: "Our findings emphasise that there is a complex interplay between genetic, epigenetic, and environmental factors that influence microglial responses in Alzheimer's disease. We found remarkable differences when comparing microglia expressing different isoforms of the same gene. Our research suggests that microglia expressing the risk-increasing APOE4 variant are not as effective at mounting protective microglial functions, including cell migration, phagocytosis and anti-inflammatory signalling. This underscores the need for targeted interventions based on APOE genotype."