🧠 The APOE4 gene that causes Alzheimer’s disease and the possibility of reversing its harmful effects on the brain

🧠 The APOE4 gene that causes Alzheimer’s disease and the possibility of reversing its harmful effects on the brain

Summary: Recent research conducted by a team from Mount Sinai University revealed new mechanisms through which the APOE4 gene, the strongest genetic risk factor for Alzheimer’s disease, contributes to damage to the brain’s blood vessels and the accumulation of harmful proteins associated with neurodegenerative diseases. The studies showed that these harms are not permanent, but can be reversed by targeting specific processes such as TGF-β signaling, opening the door to new therapeutic strategies. The team also developed a human three-dimensional model called miBrains using stem cells, which is an important tool for studying the disease and testing potential treatments.

🩺 What does the presence of APOE4 mean in Alzheimer’s disease?

The APOE4 gene is known as one of the most important genetic factors that increase the likelihood of developing Alzheimer’s disease, a degenerative disease that affects memory, cognitive functions, and behavior, and affects more than 7 million elderly people in the United States alone.

It was previously known that the blood vessels in the brain deteriorate as Alzheimer’s disease progresses, especially in carriers of the APOE4 gene, but the causes and mechanisms were not entirely clear. Many studies considered this damage to be a secondary result of the disease, not a causative element, which limited treatment focus on these aspects.

🧬 How does APOE4 affect blood vessels in the brain?

In the study published in the journal Cell, the researchers used a single-cell transcriptomic atlas to understand how APOE4 affects the cells that make up the brain’s blood vessels.

The results showed that the presence of this gene changes the behavior of a certain type of cell called pericytes, which are cells responsible for supporting blood vessels and maintaining the integrity of the blood-brain barrier.

• These cells, under the influence of APOE4, transform into muscle-like cells that overproduce scar tissue.
• This transformation results in increased blood vessel fibrosis, a condition known as vascular fibrosis.
• The fibrosis begins by encouraging the accumulation of abnormal proteins such as amyloid around blood vessels, which impedes blood flow.

These changes may contribute to creating a favorable environment for the nerve degeneration associated with Alzheimer’s disease.

🧪 The possibility of reversing damage by targeting TGF-β signaling

One of the important discoveries highlighted in the study is the researchers’ ability to reverse these changes by inhibiting a cellular signaling pathway known as TGF-β (Transforming Growth Factor Beta), a key factor in cell-to-cell communication and tissue remodeling.

• By disabling this pathway in experimental models, the researchers restored the coverage of the blood-vessel-supporting cells.
• The level of fibrosis decreased and harmful amyloid accumulation decreased.
• These results were confirmed in aged mice carrying the APOE4 gene, confirming the possibility of treating this vascular damage.

These findings show that blood vessel damage in the brain as a result of APOE4 is a biologically active process that can be treated, rather than just an irreversible side effect.

🌱 The miBrains platform for understanding and developing Alzheimer’s treatment

To deepen and strengthen their understanding, the researchers used a three-dimensional human model called miBrains; human brain tissue is reconstructed from induced pluripotent stem cells.

• These models contain multiple brain cell types, including neurons, glial cells, myelin cells, and blood-vessel-forming cells.
• They accurately mimic the human brain environment, allowing the molecular dynamics and cellular changes associated with Alzheimer’s disease to be monitored.
• This platform made it possible to reconstruct the early stages of injury before the severe changes that appear in postmortem tissue.
• It enables drugs and therapeutic approaches to be tested more efficiently and more quickly by comparing the models with data extracted from human tissue and animal models.

🧠 APOE4 and its effect on the accumulation of harmful proteins in the brain

Another study published in the journal Cell Stem Cell examined the effect of APOE4 on the storage of abnormal proteins, such as α-synuclein, a protein closely associated with Parkinson’s disease and Lewy body dementia.

The accumulation of harmful proteins is the main feature of neurodegeneration, but discovering how these proteins cause damage inside the human brain has been a major challenge.

Using the miBrains model, the researchers recorded:

• A noticeable increase in the accumulation of α-synuclein in brains carrying the APOE4 gene.
• They linked this accumulation to the buildup of lipids (fats) inside support cells called astrocytes.

🧪 Cholesterol interference and astrocyte function

Experiments showed that the presence of APOE4 leads to the accumulation of large amounts of cholesterol inside astrocytes, which disrupts the function of the lysosomal waste-disposal system responsible for breaking down and removing harmful proteins.

As a result, these cells become less able to clear α-synuclein, allowing it to accumulate and spread inside neurons, contributing to the formation of toxic deposits.

This chain of events directly links changes in cellular fat metabolism and impaired waste-removal mechanisms, identifying potential therapeutic targets for both Alzheimer’s disease and Parkinson’s disease.

🧬 miBrains in shaping the therapeutic future

The miBrains platform has another major advantage: it can be cryopreserved, which allows it to be reused in multiple experiments.

• This feature ensures stable experimental results and improves reproducibility.
• It also makes it easier to expand the scope of studies on complex diseases.
• The research team is working to develop each patient’s own miBrains, opening prospects for studying disease progression and individual differences in treatment response.

The researchers hope that this technology will make it possible to create accurate personalized models that help speed up treatment testing and assess their effectiveness on an individual basis.

🩺 In conclusion: the importance of the study and its impact on the future treatment of neurodegenerative diseases

These studies showed that the APOE4 gene affects the brain through complex mechanisms including cerebral blood-vessel fibrosis and the accumulation of harmful proteins, and that these effects are neither fixed nor permanent.

The possibility of reversing blood-vessel damage by targeting cell signaling, and linking abnormal protein accumulation to defects in cholesterol and lysosomal processes, offers a new therapeutic perspective.

The development of miBrains represents an important qualitative step toward a deeper and more detailed understanding of the disease, and contributes to developing personalized treatment methods that may lessen the burden of Alzheimer’s and Parkinson’s diseases in the future.

These discoveries remain a fundamental starting point for further research into interventions that can improve the quality of life of millions of people affected by neurodegenerative diseases around the world.

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