A new study published in the journal Nature has uncovered a new role for a gene known to be key in the development of Alzheimer’s disease: ApoE. This newly gained understanding gives researchers a novel therapeutic target, which, they hope, will soon enable them to cure the condition.
The senior author of the new study is Dr. David Holtzman, head of the Department of Neurology at the Washington University School of Medicine in St. Louis, MO. The team – led by Dr. Holtzman – investigated the effect of the ApoE4 gene variant in the development of Alzheimer’s disease.
ApoE has different variants, or alleles: e2, e3, and e4. Studies have shown that ApoE e4 (ApoE4) puts carriers at a dramatic risk of developing Alzheimer’s disease.
Additionally, studies of brain pathology have shown that people with ApoE4 have more of the amyloid beta plaques accumulated in the brain. Beta-amyloid is a sticky protein that clumps together, blocking neuron-to-neuron signaling in Alzheimer’s patients.
So, while it is known that ApoE4 is somehow crucial in Alzheimer’s disease, the mechanism whereby this gene contributes to disease formation remains unclear.
The new research by Dr. Holtzman and his colleagues sheds some light on this mechanism. Their findings suggest that ApoE4 may “work” by exacerbating the damage done by a different protein associated with Alzheimer’s: tau.
In a healthy brain, the tau protein helps to transport nutrients and other supplies to neurons. But, in a brain affected by Alzheimer’s disease, tau forms tangles, which break down this essential transport system.
Dr. Holtzman and team designed a mouse model in which the rodents had a modified form of human tau, predisposing them to tangle formation.
They genetically engineered the mice to carry human versions of the ApoE gene – namely, e2, e3, and e4 – instead of their mouse-specific ApoE.
The researchers followed the mice for 9 months. By this time, the mice that had the e4 allele showed the most neurodegeneration, while those with e2 had the least.
In the mice with ApoE variations, the hippocampus and entorhinal cortex – which are both brain regions important for memory – had atrophied. These mice also exhibited brain damage, with numerous brain cells having died.
The study found that when ApoE was not present, tau tangles were not as harmful. In fact, mice that lacked ApoE altogether did not exhibit any brain damage.
The team also found that the immune cells in the brains of mice with ApoE4 were activated, suggesting a strong inflammatory response. By contrast, mice lacking ApoE4 did not show immune cell activation.
“ApoE4 seems to be causing more damage than the other variants because it is instigating a much higher inflammatory response, and it is likely the inflammation that is causing injury,” explains Dr. Holtzman.
“But all forms of ApoE – even ApoE2 – are harmful to some extent when tau is aggregating and accumulating. The best thing seems to be in this setting to have no ApoE at all in the brain,” he adds.
To examine whether or not ApoE has the same role in human brains, the researchers examined autopsy samples from 79 people who had died from tau pathologies and inventoried the ApoE variants that these people had.
The analysis revealed that the brains of those with the e4 variant of ApoE exhibited more severe damage than those without the variant.
“Assuming that our findings are replicated by others, I think that reducing ApoE in the brain in people who are in the earliest stages of disease could prevent further neurodegeneration,” Dr. Holtzman says.
He explains that because ApoE is important for transporting cholesterol, the few people who lack the gene entirely develop cardiovascular disease as a result of cholesterol buildup.
Cognitively, however, there seems to be no obvious role for the protein. “There are people walking around who have no ApoE and they’re fine cognitively,” Dr. Holtzman says. “It doesn’t appear to be required for normal brain function.”
He notes that so far, research has focused on reducing either tau or beta-amyloid, but ApoE has not yet been targeted.
“Once tau accumulates, the brain degenerates […] What we found was that when ApoE is there, it amplifies the toxic function of tau, which means that if we can reduce ApoE levels, we may be able to stop the disease process.”
Dr. David Holtzman