Scientists at the Gladstone Institutes report that a rare genetic variant, known as the “Christchurch mutation,” can block detrimental effects of apolipoprotein E4 (APOE), the best-established risk factor for the most common form of Alzheimer’s disease (AD).
The APOE gene has long been known to affect the risk of Alzheimer’s disease through its three main variants: E2 (low risk), E3 (intermediate risk), and E4 (high risk). More recently, a genetic change in this gene, the Christchurch mutation, was identified in a woman who did not develop Alzheimer’s disease even though she had inherited another gene that causes a rare but highly aggressive form of the disease. The finding raises the possibility that the Christchurch mutation may protect against Alzheimer’s disease.
Gladstone Institutes researchers investigated whether the Christchurch mutation can also protect against the detrimental effects of APOE4, which is an important risk factor for the most common form of Alzheimer’s disease. The scientists found that engineering the Christchurch mutation into the APOE4 gene reduces the APOE4-dependent accumulation of the protein tau, neuroinflammation, and neurodegeneration in models of Alzheimer’s.
Broad protection
“It’s really exciting that the Christchurch mutation can lead to such broad protection,” said Gladstone investigator Yadong Huang, MD, PhD, senior author of the new study, “The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation,” which is published in Nature Neuroscience. “It opens the door to novel therapeutic interventions that could mimic the beneficial effects of this mutation.”
“Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation,” the investigators wrote.
“Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.”
Complex genetics
In 2019, researchers learned about the woman near Medellin, Colombia, who escaped her family’s fate of early-onset Alzheimer’s disease. She and many of her extended family carried a variant of the PSEN1 gene that causes a rare but aggressive form of early-onset Alzheimer’s. She, however, also carried another mutation—a tiny change in the APOE gene known as the Christchurch mutation. The same mutation had been identified decades earlier in a family in Christchurch, New Zealand, and was shown to have an impact on cholesterol levels and heart disease.
“It seemed likely that this woman was protected from early-onset Alzheimer’s disease because of the APOE Christchurch mutation,” said Huang, who is also director of the Center for Translational Advancement at Gladstone, and professor of neurology and pathology at the University of California, San Francisco. “We immediately wondered whether this mutation could also be protective against late-onset Alzheimer’s, which accounts for the vast majority of cases of the disease.”
Huang’s lab had already been studying the impact of APOE4 on brain cells and had developed strains of mice, whose own APOE genes were replaced with human APOE genes, and that also produce the human tau protein, which accumulates in the brain with aging and in Alzheimer’s disease.
Maxine Nelson, PhD, a former graduate student in Huang’s lab and lead author of the new paper, and her collaborators further engineered those strains of mice to also have the Christchurch mutation. They also used CRISPR gene editing to alter the APOE4 gene in human induced pluripotent stem cells, which had been generated from an Alzheimer’s disease patient’s blood cells, and then developed into mature neurons in a dish.
“It was amazing to be able to bring all these technologies together to answer a question that had significant implications for both research and patients,” said Nelson.
Expected signs of Alzheimer’s
In mice that carried human APOE4 and tau genes but lacked the Christchurch mutation, the researchers saw many of the expected signs of Alzheimer’s disease. The tau protein accumulated in neurons, levels of neuroinflammation increased in the brain, and immune cells known as disease-associated microglia became more prevalent.
Remarkably, introducing the Christchurch mutation into these mouse models prevented or markedly reduced these abnormalities.
By comparing human neurons that produced APOE4 with or without the Christchurch mutation in cell culture, the researchers were able to identify molecular mechanisms that could contribute to the beneficial effects of the mutation in brain. These mechanisms relate to the transfer of tau from the outside to the inside of neurons, which might contribute to neuronal impairments in Alzheimer’s disease. This transfer, or uptake, of tau is mediated by cell surface molecules called heparan sulfate proteoglycans (HSPGs) and, as it turns out, is strongly affected by APOE and the Christchurch mutation.
“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.”
