Protein linked to cholesterol may defeat Alzheimer’s and extend healthy lifespans

PHILADELPHIA — The ongoing medical mission to fully understand, treat, and overcome Alzheimer’s disease remains a high priority for scientists all over the world. While estimates show there are about six million Americans living with Alzheimer’s today, most studies project that figure will rise to an astounding 13 million by 2050. Now, a team at Temple University Health System has discovered a promising new therapeutic target that might defeat Alzheimer’s and extend lifespans.

More specifically, the team at the Alzheimer’s Center at Temple, at the Lewis Katz School of Medicine, says that their work has uncovered more information about ABCA7, a protein known to offer some protection from Alzheimer’s disease. This latest study details new information about the relationship connecting ABCA7, cholesterol, and inflammation in human brain cells.

Alzheimer’s has become synonymous with the term dementia in recent years, and for good reason. While there are many other forms of dementia, such as vascular or Lewy body dementia, rates of Alzheimer’s among older populations globally have risen considerably in recent years. Today, the degenerative brain disease ranks among some of the top causes of death all over the world.

Characterized by progressively worsening memory and other thinking abilities, Alzheimer’s is an awful affliction that can slowly rob an individual of their memories, and eventually, their very identity. On a more practical level, Alzheimer’s can cut patients’ careers short, foster financial and retirement uncertainty, and flat-out rob patients of enjoyment and happiness during their golden years.

While there are many drugs out there that claim to help Alzheimer’s patients manage their symptoms, and some patients do find relief through these avenues, the fact remains there is no known cure for Alzheimer’s at this time. The team behind this latest work stresses that an effective treatment against Alzheimer’s could benefit patients tremendously. For example, by allowing more personal control over when to retire, or simply offering a better quality of life.

Confused older man
Confused senior man with dementia looking at a wall calendar (© highwaystarz – stock.adobe.com)

The key role of ABCA7 in the development of Alzheimer’s disease was first uncovered by a series of genome-wide association studies, which are large-scale investigations of the human genome encompassing thousands of participants.

“But genome studies only point to a protein and do not tell us anything about how it functions or how it affects a disease,” says Joel Wiener, an investigator with the Alzheimer’s Center at Temple and first study author, in a university release. “Our goal is to reveal ABCA7’s functions and to use what we learn about its role in pathology to turn it into an effective therapy against Alzheimer’s disease.”

Earlier studies conducted by Nicholas Lyssenko, Ph.D. an investigator at the Alzheimer’s Center at Temple and corresponding author of the new study, already revealed that people between the ages of 63 and 78 exhibiting low ABCA7 protein levels in the brain are at a greater risk of Alzheimer’s disease. That finding in particular helped to validate earlier genome studies that reached similar conclusions, and even took the insights a step further, suggesting the protein protects the human brain.

For this newest work, Dr. Lyssenko’s team looked to address how cholesterol metabolism and inflammation may end up influencing ABCA7 levels in human brain cells, consequently affecting Alzheimer’s disease progression. For example, one set of experiments entailed researchers depleting cholesterol in different neural cell lines, such as microglia, astrocytes, and neurons, and then treating the cells with rosuvastatin, a medication known to suppress cholesterol synthesis.

Next, in an effort to gauge the effect of inflammation on ABCA7, study authors put together another set of experiments that featured the same cell lines being treated with one of three major proinflammatory cytokines: IL-1β, IL-6, or TNFα. Cytokines, for reference, are small molecules that trigger inflammation following their secretion from different varieties of immune cells.

All in all, researchers discovered that ABCA7 levels dropped by roughly 40 percent in microglia cell lines and about 20 percent in an astrocyte cell line after the cells had been depleted of more than half their typical cholesterol levels. On the other hand, the team did not see any changes with regard to ABCA7 levels in a neuronal cell line following cholesterol loss. Also, IL-1β and TNFα suppressed ABCA7 expression but only in microglial cells. Interestingly, the third cytokine, IL-6, showed no impact at all on ABCA7 in microglia. Meanwhile, none of the three included three cytokines induced any changes in ABCA7 levels across either astrocytes or neurons.

Cholesterol test -- results show high cholesterol
(© jarun011 – stock.adobe.com)

In conclusion, study authors say these findings advance in a major way our overall understanding of how ABCA7 is regulated in the brain.

“Our findings suggest that cholesterol loss downregulates ABCA7 in many cells in the human brain. Previous work in mice showed that cholesterol loss upregulates ABCA7,” Mr. Wiener explains. “In addition, other investigators found that inflammation suppresses ABCA7 in astrocytes, and we show now that this can also happen in microglia. Overall, cholesterol depletion and inflammation may reduce ABCA7 levels in the brain and cause the onset of Alzheimer’s disease.”

Moving forward, the team at Temple aims to take multiple approaches when it comes to studying ABCA7; human cells will be experimented on, but further efforts will also involve animal models and postmortem human brain tissue.

“The greatest challenge now is to figure out how to measure ABCA7 levels in the brain of living humans,” Dr. Lyssenko concludes. “If we achieve this, we could verify whether inflammation suppresses ABCA7 in the human body. Effective testing for ABCA7 levels in the brain will also identify individuals who are at greater risk for Alzheimer’s disease and spur the development of new ABCA7-based therapies.”

The study is published in the journal Cells.

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