With a clinical trial failure rate of 99% over the past 15 years or so, the path to a cure for Alzheimer’s disease is riddled with disappointment. In many cases, candidate therapies looked very promising in pre-clinical animal studies, only to flop when tested in people. Now, a CIRM-funded Nature Medicine study by researchers at the Gladstone Institutes sheds some light on a source of this discrepancy. And more importantly, the study points to a potential treatment strategy that can remove the hallmarks of Alzheimer’s in human brain cells.

Build up of tau protein (blue) and amyloid-beta (yellow) in and around neurons are hallmarks of the damage caused by Alzheimer’s disease. 
Image courtesy of the National Institute on Aging/National Institutes of Health.

For several decades, researchers have known the ApoE gene can influence the risk for an Alzheimer’s diagnosis in individuals 65 years and older. The gene comes in a few flavors with ApoE3 and ApoE4 differing in only one spot in their DNA sequences. Though nearly identical, the resulting ApoE3 and E4 proteins have very different shapes with differing function. In fact, people who inherit two copies of the ApoE4 gene have a twelve times higher risk for Alzheimer’s compared to those with the more common ApoE3.

Yadong Huang

To better understand what’s happening at the cellular level, Yadong Huang, PhD and his team at the Gladstone Institutes obtained skin samples from Alzheimer’s donors carrying two copies of the ApoE4 gene and healthy donors with two copies of ApoE3. The skin cells were reprogrammed into induced pluripotent stem cells (iPSCs) and then matured into nerve cells, or neurons.

Compared to ApoE3 cells, the researchers observed that the ApoE4 neurons accumulated higher levels of proteins called p-tau and amyloid beta, which are hallmarks of Alzheimer’s disease. Repeating this same experiment in iPSC-derived mouse neurons showed no difference in the production of amyloid beta levels between the ApoE3 and E4 neurons. This result points to the importance of studying human disease in human cells, as first author Chengzhong Wang, PhD, points out in a press release:

“There’s an important species difference in the effect of apoE4 on amyloid beta. Increased amyloid beta production is not seen in mouse neurons and could potentially explain some of the discrepancies between mice and humans regarding drug efficacy. This will be very important information for future drug development.”

Further experiments aimed to answer a long sought-after question: is it the absence of ApoE3 or the presence of ApoE4 that causes the damaging effects on neurons? Using gene-editing techniques, the team removed both ApoE forms from the donor-derived neurons. The resulting cells appeared healthy but when ApoE4 was added back in, Alzheimer’s-associated problems emerged. This finding points to the toxicity of ApoE4 to neurons.

With this new insight in hand, the team examined what would happen if they converted the ApoE4 form into the ApoE3 form. The team had previously designed molecules, they dubbed “structure correctors”, that physically interact with the ApoE4 protein and cause it to take on the shape of the ApoE3 form found in healthy individuals. When these correctors were added to the ApoE4 neurons, it brought back normal function to the cells.

Given that the structure corrector is a chemical compound that works in human brain cells, it’s tantalizing to think about its possible use as a novel Alzheimer’s drug. And you can bet Dr. Huang and his group are eagerly embarking on that new path.