Variants in the ApoE gene are the strongest genetic risk factor there is for developing Alzheimer’s disease. Inheriting the E2 allele decreases the number of plaques, while inheriting the E4 allele increases the number of plaques and raises the risk of developing Alzheimer’s disease – for those unlucky individuals who have two copies, that risk jumps by 12-fold. E4 carriers also start developing the disease decades earlier than those with E2 alleles.
So far, so good. “That observation . . . is 20 years old,” Massachusetts’ General Hospital’s Bradley Hyman told BioWorld Today.
But exactly how ApoE mediates the risk of Alzheimer’s disease has remained unknown. ApoE binds to amyloid beta, the component of amyloid plaques that are the anatomical hallmark of Alzheimer’s disease. But what happens once the two are bound, he said, “hasn’t been well described.”
In the Nov. 21, 2013, issue of Science Translational Medicine, Hyman and his colleagues offer “a little more insight into how that risk is mediated.”
In a nutshell, the scientists used gene therapy to deliver different ApoE alleles to the brains of mice prone to Alzheimer’s disease. In doing so, they have gained new insights into how ApoE affects the amounts and distribution of amyloid beta, and the amyloid plaques it forms.
They have also shown that gene therapy vector delivered to the cerebrospinal fluid cells was taken up by the cells that line the cerebral ventricles, and the ApoE produced by those cells ultimately made it to much of the brain, via the cerebrospinal and interstitial fluids.
In their studies, Hyman and his team looked at the effects of the three variants of ApoE – E2, E3 and E4 – on amyloid beta levels and plaques in the brains of Alzheimer’s mice. By treating the animals at a time when plaque formation had already begun, they were able to see whether different forms of the protein speeded up or slowed down the formation of plaques in the animals’ brains.
They found that animals treated with the protective E2 variant had lower levels of both soluble oligomers, which are an intermediate toward plaque formation, and plaques themselves than animals treated with E3. E4-treated animals had the highest levels of both forms of amyloid. The most likely explanation for the results is that different forms of ApoE bind to and clear amyloid beta plaques at different rates, though how the variants differ in their binding has not been worked out.
The studies suggested that boosting ApoE2 levels in the brain, or lowering levels of ApoE4, might be a useful approach in slowing down the progression of Alzheimer’s disease. Hyman said his team plans to look at whether there is long-term improvement in the mice, as well as whether there are problems with increasing the levels of even “good” ApoE2 that might become apparent only after a time.
The study also shows that it may be possible to use gene therapy directed at the cells lining the cerebral ventricles to produce secreted proteins, even if those proteins are not normally produced by those cells. Brain ApoE, for example, is normally produced by astrocytes.
Hyman cautioned that the approach would need to be tested in larger animals. “Would it work in larger brains, where it would have to diffuse further from the ventricles?” is an open question for now. In regenerative medicine, for example, some interventions are successful in rats but not in humans, simply because an axon in an injured spinal cord might have to travel 10 times as far in the latter to reconnect with its target.
But potentially, the method could be a way to bring secreted proteins to the brain without leaving it like Swiss cheese. Astrocytes are widespread in the brain, and transforming them, he said, would necessarily be restricted to a few locations – “you certainly can’t make tracks in the brain every 5 millimeters” to deliver the gene therapy.