Researchers at the Gladstone Institutes have made a pivotal discovery in Alzheimer’s disease genetics. They found that the Christchurch mutation in the APOE gene offers protection against the harmful effects of the APOE4 allele, a significant risk factor for Alzheimer’s. This groundbreaking research, demonstrating diminished neurodegeneration in Alzheimer’s models, introduces new avenues for therapeutic approaches. The findings were published in the esteemed journal, Nature Neuroscience.
This novel study brings to light the defensive actions of the “Christchurch mutation.”
The team at Gladstone Institutes unearthed that the “Christchurch mutation,” a rare genetic variation, can counter the adverse effects of apolipoprotein E4 (APOE4), the leading risk factor for the most prevalent type of Alzheimer’s disease.
The apolipoprotein E (APOE) gene, with its three primary variants—E2 (low risk), E3 (intermediate risk), and E4 (high risk)—has been acknowledged for its role in Alzheimer’s disease risk. The “Christchurch mutation,” observed in a woman who didn’t develop Alzheimer’s despite carrying a gene for a rare, severe form of the disease, hinted at a possible protective role against Alzheimer’s.
Pioneering Study on the Christchurch Mutation
The Gladstone Institutes’ research focused on whether the Christchurch mutation could also mitigate the detrimental impacts of APOE4, a key risk factor for the common variant of Alzheimer’s. The researchers demonstrated that introducing the Christchurch mutation into the APOE4 gene lessens APOE4-induced tau protein accumulation, neuroinflammation, and neurodegeneration in Alzheimer’s disease models.
The research, led by a team including Maxine Nelson and Yadong Huang at Gladstone, uncovers the protective mechanisms of the “Christchurch mutation.” This work was highlighted in Nature Neuroscience on November 13.
Yadong Huang, MD, PhD, a senior author of the study and Gladstone Investigator, expressed excitement about the broad protective potential of the Christchurch mutation, opening prospects for new therapeutic strategies that could replicate its beneficial effects.
Decoding the Mutation’s Origins and Influence
In 2019, researchers learned about a Colombian woman near Medellin who avoided the early-onset Alzheimer’s prevalent in her family. She carried both a variant of the PSEN1 gene, linked to an aggressive form of early-onset Alzheimer’s, and the Christchurch mutation in the APOE gene. This mutation was previously identified in a New Zealand family and found to influence cholesterol levels and heart disease.
Huang, also the director of the Center for Translational Advancement at Gladstone and a professor at UC San Francisco, speculated that the Christchurch mutation shielded the woman from early-onset Alzheimer’s and possibly from the more common late-onset form.
Huang’s lab, already studying APOE4’s effects on brain cells, used mice with human APOE genes and the human tau protein. These mice models were further modified by Maxine Nelson, PhD, and her team to include the Christchurch mutation. They also employed CRISPR gene editing on human induced pluripotent stem cells derived from an Alzheimer’s patient, converting them into mature neurons for study.
Nelson highlighted the significance of integrating various technologies to address a question with profound implications for research and patient care.
Elucidating Protection Mechanisms
In mice with human APOE4 and tau genes but lacking the Christchurch mutation, typical Alzheimer’s symptoms were observed. However, introducing the Christchurch mutation into these models significantly reduced or prevented these issues.
Studying human neurons with and without the Christchurch mutation in APOE4, the researchers identified molecular mechanisms that might explain the mutation’s positive effects on the brain. These mechanisms involve the transfer of tau protein into neurons, a process impacted by cell surface molecules called heparan sulfate proteoglycans (HSPGs) and influenced by APOE and the Christchurch mutation.
The study found that the Christchurch mutation considerably reduces APOE4’s binding to HSPGs, leading to decreased neuronal tau uptake.
Huang suggested that inhibiting APOE4’s interaction with HSPGs could be key in treating or preventing Alzheimer’s in individuals with the APOE4 gene, potentially through small molecule drugs, monoclonal antibodies, or gene therapy. However, he noted that further research is necessary to develop and test such treatments.
This significant research was published in Nature Neuroscience on November 13, 2023, under the title “The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration, and neuroinflammation.”
The study included contributions from various authors and was supported by the National Institutes of Health, Open Philanthropy, and Good Ventures.
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Frequently Asked Questions (FAQs) about Christchurch mutation Alzheimer’s
What is the Christchurch mutation in Alzheimer’s disease genetics?
The Christchurch mutation is a rare genetic variant in the APOE gene that has been found to protect against the harmful effects of the APOE4 allele, a significant risk factor for Alzheimer’s disease. This discovery was made by researchers at the Gladstone Institutes and suggests new possibilities for Alzheimer’s disease treatment and prevention.
How does the Christchurch mutation impact Alzheimer’s disease?
The Christchurch mutation in the APOE gene reduces the accumulation of the tau protein, neuroinflammation, and neurodegeneration in Alzheimer’s disease models. This indicates its potential to counteract the detrimental effects of the APOE4 gene variant, which is a major risk factor for the most common form of Alzheimer’s disease.
What are the implications of the Gladstone Institutes’ study on Alzheimer’s?
The study by the Gladstone Institutes opens up new avenues for therapeutic approaches in Alzheimer’s disease. By demonstrating the protective role of the Christchurch mutation against the effects of APOE4, it provides a basis for developing treatments that could mimic this beneficial effect, potentially leading to novel strategies for combating Alzheimer’s.
How was the Christchurch mutation studied in relation to Alzheimer’s?
The research involved engineering mice models and human induced pluripotent stem cells to include the Christchurch mutation. This allowed the researchers to observe the mutation’s effects on the brain and identify molecular mechanisms that contribute to its protective role in Alzheimer’s disease, particularly in relation to the tau protein and neuroinflammation.
More about Christchurch mutation Alzheimer’s
- Gladstone Institutes Research
- APOE Gene and Alzheimer’s
- Christchurch Mutation in Alzheimer’s
- Nature Neuroscience Publication
- Alzheimer’s Disease Genetics
- Neurodegeneration and APOE4
- Alzheimer’s Treatment Advances
- Gene Therapy in Alzheimer’s Research
