Genetic mutations that happen in a gene called apolipoprotein E (APOE) have long been known to have a significant impact on the risk of Alzheimer's disease. Variants of the gene are have different effects; a variant known as E2 carries a low risk of Alzheimer's disease, E3 an intermediate risk, and E4 is high risk. A rare genetic variant has now been shown to prevent the increased risk of Alzheimer's disease caused by APOE4. The findings have been reported in Nature Neuroscience.
This study was made possible because of a woman who inherited a genetic mutation (in a gene called PSEN1) that causes an unusually aggressive form of Alzheimer's. But unlike others in her family, she did not get the disease. Researchers had found that she carried what has been called the 'Christchurch mutation.' In this studym the scientists wondered if this mutation could also protect against the detrimental impact of APOE4. They found that it did.
"It's really exciting that the Christchurch mutation can lead to such broad protection," said senior study author Yadong Huang, MD, PhD, an Investigator at Gladstone Institutes, among other appointments. "It opens the door to novel therapeutic interventions that could mimic the beneficial effects of this mutation."
The Christchurch mutation was originally identified in members of a Christchurch, New Zealand family. It can affect cholesterol levels and heart disease. In this study, it was introduced into a mouse model in which the mouse APOE genes has already been replaced with the human version of APOE, so that variants would cause the tau accumulations in the brain that have been linked to Alzheimer's. These mice then carried the Christchurch mutation as well as the APOE4 variant. This strategy was repeated in neurons that had been generated from induced pluripotent stem cells. Those stem cells had been obtained from an Alzheimer's disease patient.
When mice had both human APOE4 and tau genes but did not have the Christchurch mutation, symptoms of Alzheimer's disease appeared; tau accumulations formed, neuroinflammation increased, and levels of microglia, which are immune cells in the brain, increased.
But the presence of the Christchurch mutation reduced or prevented tau buildup, neuroinflammation, and neurodegeneration.
The investigators determined that the uptake of tau into neurons involves molecules called heparan sulfate proteoglycans (HSPGs) on cell surfaces. This mechanism was found to be significantly influenced by APOE.
Many years ago, it was shown that HSPGs and APOE interact. This work has shown that binding between APOE4 and HSPGs is reduced strongly when the Christchurch mutation is present; this significantly lowered the uptake of tau into neurons.
"The results suggest that blocking the interaction of APOE4 with HSPGs could help treat or prevent Alzheimer's disease in people with the APOE4 gene," Huang said. "This might be accomplished with small molecule drugs, monoclonal antibodies, or gene therapy. However, more work is needed before such treatments can be developed and tested."
Sources: Gladstone Institutes, Nature Neuroscience
