If you have one copy of a gene called apoE4, then your chances of developing Alzheimer’s disease are more than doubled. Moreover, if you carry two copies of apoE4, then you have a 12-fold risk of developing Alzheimer’s disease.
Remarkably, some brilliant researchers have found a way to neutralize apoE4, albeit that the research is still in the early stages. You’ll find the details published in Nature Medicine.
Beta Amyloid and Alzheimer’s Disease
A build up of a protein called beta amyloid (Aβ) occurs in Alzheimer’s disease and it can be toxic to nerves. Apolipoprotein E (apoE) regulates Aβ. ApoE has three common alleles (ε2, ε3, ε4) that encode three isoforms (apoE2, apoE3, apoE4). To put it another way, the apoE gene has three variants that express three different types of apoE, the problematic one being apoE4.
Furthermore, while humans have three alleles of apoE, most other mammals only have one allele. This difference turns out to be critical. It accounts for the failure of animal studies to replicate the human situation; more on that below.
The Problem with the Mouse Model of Alzheimer’s Disease
The most widely used animal model for studying Alzheimer’s disease is the “murine” model, based on the humble mouse. Normally, we test the potential benefits of candidate drugs using the mouse model. Critically, Huang and colleagues also showed that these effects do not occur in the mouse model of Alzheimer’s disease. Specifically, in mice, apoE4 did not increase Aβ levels, but in humans apoE4 significantly increases Aβ levels. So, using mice does not tell us what we need to know.
Pluripotent Stem Cells
Therefore, they bypassed the mouse model by using pluripotent stem cell technology. Alzheimer’s patients who were already known to have two copies of the apoE4 gene donated skin samples. The researchers used those samples to create neurons to study these effects. If you would like to know more about pluripotent stem cells, head on over to the Allen Cell Explorer.
Interestingly, the isoforms of apoE (apoE2, apoE3 and apoE4) are 299-amino acid proteins that differ at only two locations, positions 112 and 158. Amazingly, Yadong Huang and colleagues from the Gladstone Institutes have figured out how to convert apoE4 protein into apoE3 protein. They achieved this by using gene editing. Cleverly, they added a small molecule that corrects a structural defect in apoE4. That ploy has the effect of transforming apoE4 into apoE3.
