What’s the Issue with APOE?

The APOE gene encodes apolipoprotein E, a protein involved in lipid transport within the body. It facilitates the movement of fat-soluble vitamins and aids in transporting lipid waste produced by neurons to astrocytes, another type of brain cell, for processing. In essence, APOE functions as a small shuttle for fats throughout the body.

However, the APOE4 variant of this protein can lead to severe complications within the brain. Interestingly, it may have some beneficial effects early in life. Over time, though, APOE4 can overwhelm astrocytes with lipid waste, weaken the blood-brain barrier, escalate inflammation, harm the myelin sheath surrounding neurons, and contribute to the formation of tau tangles, which are characteristic of neurodegenerative diseases.

Could We Remove APOE4?

In a recent study, researchers examined the effects of selectively eliminating APOE4 from neurons on the development of tau pathologies in mouse models. The term "selectively" is key here; while APOE has essential functions, removing it entirely is not advisable. Instead, targeting the locations where APOE4 causes damage could be a more effective strategy.

To test this, scientists genetically modified mice to express an enzyme known as Cre recombinase, which can be customized to delete the APOE gene. They ensured that this enzyme is activated only in the presence of a neuron-specific DNA sequence (the synapsin-1 promoter). As a result, the enzyme significantly reduced APOE gene expression in neurons while leaving it unchanged in other brain cell types.

What were the outcomes for the APOE4 mice when the expression of APOE4 was inhibited in neurons?

• A dramatic reduction of approximately 81% in tau pathology compared to typical APOE4 mice.
• The remaining tau tangles (around 19%) spread at a slower rate.
• Reduced neurodegeneration and diminished damage to the myelin sheath, which is crucial for efficient signal transmission.
• Neural networks operated effectively, as opposed to becoming "hyperexcitable," which is common in many tau-related diseases.
• A notable decrease in gliosis, which is the proliferation of glial cells in response to injury, akin to scar formation in the brain.
• An increase in protective astrocytes and a decline in disease-associated ones, similar improvements were observed for microglia, the brain's immune cells.

The researchers concluded that neuronal APOE4 plays a pivotal role in the pathogenesis of APOE4-related Alzheimer’s disease and should be considered as a target for therapeutic interventions aimed at mitigating the harmful effects associated with APOE4 in Alzheimer’s and other tauopathies.

Caveats to Consider

It is essential to approach these findings with caution:

• Genetically modified mice do not replicate human biology perfectly. The progression of Alzheimer's and related tauopathies often involves unique human-specific factors that may not be easily replicated in animal studies.
• The study did not assess the impact of APOE4 removal on lifespan, cognitive function, or behavior.
• There may be other unmeasured effects resulting from the suppression of neuronal APOE4, which are important to consider.

This research adds another layer to the intricate puzzle of Alzheimer’s understanding.

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