The APOE gene is a major genetic risk factor for Alzheimer’s disease, with three different versions: APOE2, APOE3, and APOE4. While APOE4 increases the risk of developing Alzheimer’s, APOE2 is associated with a lower risk. However, how these isoforms lead to strikingly different risk profiles is poorly understood.

A recent study published in Nature Communications offers clues into how APOE isoforms differentially affect human microglia function in Alzheimer’s disease. The study, led by Dr. Sarah Marzi and Dr. Kitty Murphy at the UK Dementia Research Institute at King’s College London and the Department of Basic and Clinical Neuroscience, underscores the need for new targeted interventions based on APOE genotypes.

The researchers developed a human “xenotransplantation model,” where human microglia were grown from stem cells, manipulated to express different APOE versions, then transplanted into the brains of mice that had developed a buildup of amyloid plaques. The microglia were then isolated and analyzed for their gene expression (using transcriptomics) and chromatin accessibility.

The study uncovered widespread changes to the transcriptomic and chromatin landscape of microglia, dependent on the APOE isoform expressed. The largest differences were observed when comparing the APOE2 and APOE4 microglia.

In APOE4 microglia, researchers saw an increase in the production of cytokines, signaling molecules involved in immune regulation. They also observed diminished capacity for the microglia to migrate and shift into protective states. Furthermore, the microglia became less effective in phagocytosis, a process by which they digest and clear up particles such as debris and pathogens.

Conversely, APOE2 microglia showed increased expression of various genes that increase microglia proliferation and migration, and a decreased inflammatory immune response. Additionally, APOE2 microglia showed increased DNA-binding of the vitamin D receptor. Low levels of vitamin D have been associated with a higher incidence of Alzheimer’s.

The study highlights that microglia responses to amyloid pathology differ significantly across APOE versions. This finding underscores that considering the interplay between genetic risk factors and microglial states is critical in disease progression. The study also highlights the potential role of the vitamin D receptor, providing new avenues for therapeutic exploration.

Dr. Sarah Marzi, Senior Lecturer in Neuroscience at King’s College London and lead author of the study, said: “Our findings emphasize that there is a complex interplay between genetic, epigenetic, and environmental factors that influence microglial responses in Alzheimer’s disease. We found remarkable differences when comparing microglia expressing different isoforms of the same gene. Our research suggests that microglia expressing the risk-increasing APOE4 variant are not as effective at mounting protective microglial functions, including cell migration, phagocytosis and anti-inflammatory signaling. This underscores the need for targeted interventions based on APOE genotype.”

Breaking Ground in ALS Research: Uncovering Early Signs of Disease and New Treatment Targets

Researchers at Stockholm University and the UK Dementia Research Institute (UK DRI) have made a groundbreaking discovery that could revolutionize the treatment of Amyotrophic Lateral Sclerosis (ALS). The study, published in Nature Communications, reveals that ALS-linked dysfunction occurs in the energy factories of nerve cells, called mitochondria, before the cells show other signs of disease.

“We show that the nerve cells, termed motor neurons, that will eventually die in ALS have problems soon after they are formed. We saw the earliest sign of problems in the cell’s energy factories, the mitochondria, and also in how they are transported out into the nerve cells’ long processes where there is a great need for them and the energy they produce,” says Dr Eva Hedlund at Stockholm University, head of the study together with Dr Marc-David Ruepp at the UK Dementia Research Institute.

The research team used the gene scissors CRISPR/Cas9 to introduce various ALS-causing mutations into human stem cells, called iPS cells. From these, motor neurons and interneurons were produced, which were then analyzed with single-cell RNA sequencing. The data obtained showed a common disease signature across all ALS-causing mutations, unique to motor neurons.

This happened very early and was completely independent of whether the disease-causing mutated proteins (FUS, or TDP-43) were in the wrong place in the cell or not. “Until now, it has been believed that it is the change where the proteins are within the cells, called mislocalization, that occurs first,” says Dr Marc-David Ruepp.

The researchers also found that most errors arising from ALS-causing mutations are caused by a new toxic property of the protein, not by a loss of function. A third discovery was that the transport of mitochondria out into the axons is radically affected in the ALS lines, independently of whether the disease-causing proteins were in the wrong place in the cell or not.

The new discoveries open up for early treatment methods, something that for the research team is a continuous work in progress. “We are trying to understand how these early errors occur in the sensitive motor neurons in ALS, and how it affects energy levels in the cells and their communication and necessary contacts with muscle fibers,” says Dr Eva Hedlund.

The study’s findings have significant implications for ALS treatment and provide new targets for therapies. The research team is now working on understanding the mechanisms behind these early errors and how to address them, hoping to improve the lives of people affected by this devastating disease.

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Mitochondrial diseases affect approximately 1 in 5,000 people worldwide, causing debilitating symptoms ranging from muscle weakness to stroke-like episodes. These conditions result from mutations in mitochondrial DNA (mtDNA), which is housed in the mitochondria, the powerhouses of cells. For patients with the common m.3243A>G mutation, treatments remain limited. A fundamental challenge in mitochondrial disease research is that patients typically have a mix of both normal and mutated mtDNA within their cells, known as heteroplasmy.

This condition makes targeted therapies difficult to develop, as the normal-to-mutated mtDNA ratios can vary greatly from tissue to tissue. Current basic research into mtDNA mutations faces significant obstacles due to a lack of disease models. The complex relationship between mutation load and disease severity remains poorly understood because there are no tools to precisely manipulate heteroplasmy levels in either direction.

Against this backdrop, a research team led by Senior Assistant Professor Naoki Yahata from the Department of Developmental Biology, Fujita Health University School of Medicine, Japan, has developed a technology that can modify heteroplasmy levels in cultured cells carrying the m.3243A>G mutation. Their paper was made available online on March 20, 2025, and will be published in Volume 36, Issue 2 of the journal Molecular Therapy Nucleic Acids on June 10, 2025.

The researchers established cultures of patient-derived induced pluripotent stem cells (iPSCs) containing the m.3243A>G mutation and designed two versions of their mtDNA-targeted platinum transcription activator-like effector nucleases (mpTALENs). One version targets mutant mtDNA for destruction, while the other targets normal mtDNA. This bi-directional approach allowed them to generate cells with mutation loads ranging from as low as 11% to as high as 97%, while still maintaining the cells’ ability to differentiate into various tissue types.

The researchers also employed additional techniques, such as uridine supplementation, to establish stable cell lines with different mutation loads. Their results demonstrate that their mpTALEN optimization process created a useful tool for altering heteroplasmy levels in m.3243A>G-iPSCs, improving their potential for studying mutation pathology.

Overall, the study represents a significant advancement in mitochondrial medicine for several reasons. It provides researchers with multiple isogenic cell lines that differ only in their level of heteroplasmy, allowing for a precise study of how mutation load affects disease manifestation. The mpTALEN technology may become therapeutically valuable for reducing mutant mtDNA load in patients.

The proposed method could be adapted for other mutant mtDNAs and may contribute to understanding their associated pathologies and developing new treatments, potentially benefiting patients with various forms of mitochondrial disease.