A new study helps explain why having ApoE4 – the gene variant most closely linked to Alzheimer’s disease – increases the risk of neurodegeneration and white matter damage. Researchers at Weill Cornell Medicine found that immune cells in the brain called border-associated macrophages (BAMs) are a source of ApoE4 protein and contribute to the damage of blood vessels and brain tissue.
The study, published September 18 in Nature Neuroscience, could help scientists identify new approaches to preventing or treating Alzheimer’s disease in people who carry the ApoE4 gene and other forms of age-related brain diseases.
The APOE gene codes for apolipoprotein E (ApoE), which plays many roles in the brain. It also has several common variants (ApoE2, ApoE3 and ApoE4), of which ApoE4 increases the risk of Alzheimer’s disease up to 12-fold. ApoE4 also increases the risk of white matter damage underlying vascular dementia, the second most common cause of cognitive impairment after Alzheimer’s disease. However, how ApoE4 produces these harmful effects on the brain is not entirely clear.
Our study points to border-associated macrophages as a crucial mediator of these harmful effects and helps us understand how ApoE4 may contribute to the damage of blood vessels and brain tissue in patients with Alzheimer’s disease or other forms of age-related brain disease caused by damage to the brain. white matter.”
Dr. Laibaik Park, co-senior author of the study, associate professor of research in neuroscience at the Brain and Mind Research Institute, Weill Cornell Medicine
Deadly chain reaction
“We previously showed in another model that the amyloid beta protein that accumulates in the brains of Alzheimer’s disease patients interacts with a protein receptor on BAMs,” said Dr. Antoine Anfray, neuroscience instructor at the Feil Family Brain and Mind Research Institute. at Weill Cornell Medicine, and first author of the study. This causes a chain reaction that damages blood vessels, preventing them from clearing amyloid, leading to degeneration of brain tissue.
In their latest study, the researchers show that preclinical models genetically engineered to express the human ApoE4 variant developed reduced blood vessel and tissue damage in their brains, while those with the more benign ApoE 3 remain healthy. They discovered that BAMS with the ApoE4 variant produces inflammatory free oxygen radicals that damage blood vessels. As a result, the blood flow needed to remove waste products and repair damage to brain tissue is limited.
Surprisingly, they did not experience this damaging cascade when the BAMs were deleted from the animal models with the ApoE4 variant. The study also showed that the BAMs are not only the mediators of the damage caused by ApoE4, but also the source of ApoE4 that causes the damage. Accordingly, reducing ApoE4 expression in BAMs eliminated the deleterious vascular effects.
“These findings show that BAMs are both the source and target of the ApoE4 that causes blood vessel damage,” said study senior author Dr. Costantino Iadecola, director and chairman of the Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology. at Weill Cornell Medicine.
The researchers further confirmed that ApoE4 and BAMS transferred to animal models that did not have the ApoE4 variant developed damage to blood vessels and tissue. Alternatively, transplanting BAMS from animals with the APOE3 variant to animals with the APOE4 variant could reverse the damage.
ApoE4 contributes to a serious adverse effect of anti-amyloid treatment
The findings may help explain why some patients are more likely to experience harmful swelling and bleeding in the brain when treated with amyloid-removing antibody drugs such as Lecanemab, a complication most common in patients with ApoE4. This complication, called amyloid-related imaging abnormality (ARIA), requires treatment to be stopped, limiting its benefits in slowing the progression of early-stage Alzheimer’s disease.
Understanding how blood vessels are more fragile in some patients could help scientists develop ways to prevent this adverse effect by suppressing the production of ApoE4 by BAMs. Dr. Iadecola and Park are working to develop such interventions, but caution that more work is needed before the findings can be applied in the clinic.
For now, they are looking for ways to block the receptors that cause ApoE4-related damage to blood vessels to reduce or prevent the genetic variant’s harmful effects on the amyloid beta clearance pathway.
“We now know that ApoE4 from border-associated macrophages increases blood vessel damage, but the next step would be to actually find a way to target the macrophages to improve amyloid and tau clearance. Could it be genetically switching from ApoE4 to the ApoE3 genetic variant will better remove amyloid buildup? That will be a proof-of-concept,” said Dr. Iadecola.
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Magazine reference:
Anfray, A., et al. (2024). A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury. Nature Neuroscience. doi.org/10.1038/s41593-024-01757-6.