Damage Done by Alzheimer’s Risk Gene May Be Undone by Another Disease-Linked Gene

PET scan of a human brain with Alzheimer’s disease. (Photo by US National Institute on Aging, Alzheimer’s Disease Education and Referral Center)

(CN) — New research suggests that the most significant risk-gene associated with Alzheimer’s disease can hinder a crucial process in a specific type of brain cell — and the key to alleviating the illness may lie in an associated gene.

For decades researchers and scientists have long labored to better understand Alzheimer’s disease, an uncurable condition that currently afflicts over 5 million Americans, and yet persistent questions linger over how the tragic disease begins and behaves within the human brain.

One such question that has continually baffled scientists relates to the APOE gene, a protein that helps to metabolize and manage fats in the body. Researchers have specifically sought to explore a special variant of this gene known as APOE4, a gene roughly a quarter of people possess that puts them at a significantly greater risk for Alzheimer’s disease when compared to the slightly more common APOE3 gene type.

While this link is seemingly well established and has been long reported on, researchers have made little progress in recent decades in unraveling why this relationship between APOE4 and Alzheimer’s disease exists — until today.

In a study published Tuesday in Cell Reports, scientists based at The Picower Institute for Learning and Memory at MIT and the Whitehead Institute for Biomedical Research have uncovered evidence suggesting that when APOE4 is present in an individual, the person’s astrocytes — the most common non-neuron cell in the brain – that pay the price. Researchers found APOE4 makes it more difficult for astrocytes to gather materials in from the outside of the cell that are crucial to the cell’s strength.

When this process known as endocytosis is so severely hindered, researchers say brain circulation, communication between neurons and even the maintenance of the blood-brain barrier all take a significant and potentially devastating hit.

Researchers report, however, that there is a surprising counterweight to the consequences of APOE4: another Alzheimer’s-associated gene.

Using a series of lab experiments with cultures of stem cell-derived human astrocytes and genetically engineered yeast, researchers sought to discover if there was any cell in the human brain that could potentially fix some of the endocytosis-related issues caused by APOE4. After discovering the yeast-based protein known as Yap1802p could make up for the protein deficiencies caused by APOE4, researchers found a similar cell in humans known as PICALM that could fulfill the same purpose.

While the PICALM is known for playing a notable role in affecting Alzheimer’s disease risk, researchers determined that if you overexpress PICALM in APOE4 astrocytes, it mostly resolves the issues with proper cell management.

Priyanka Narayan, a researcher at the National Institutes of Health who co-led the study, said that while it is challenging to find the right drugs to achieve this desired effect, these results could nonetheless help researchers better assess disease risk for those with certain genetic profiles.

“Given that APOE4 carriers represent a significant proportion of AD patients, this functional interaction between APOE4 and PICALM could be relevant to assessing their level of disease risk,” Narayan said with the release of the study. “It also gives an example of how the genetic background of an individual can interact and potentially modulate the detrimental effects of the APOE4 genotype.”

Narayan further says that beyond achieving a better understanding of disease risk, these results could also give researchers invaluable insight into how the human brain’s cellular biology can aid or hinder the ongoing fight against Alzheimer’s disease.

“The techniques and systems used in this study can be used to systematically interrogate combinations of risk factors or protective factors to understand their impacts on cell biology,” the study states. “Given the genetic heterogeneity of AD and other late-onset neurodegenerative diseases, such studies will offer opportunities for genetic stratification, as well as the identification of targeted therapies for such complex diseases.”

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