Alzheimer’s disease, a devastating condition characterized by memory loss and cognitive decline, has become a leading cause of death in recent decades. Researchers at the Alzheimer’s Center at Temple University’s Lewis Katz School of Medicine are investigating a promising therapeutic target called ABCA7, a protein known to protect against Alzheimer’s disease.
A recent study published in the journal Cells sheds light on the intricate relationship between ABCA7, cholesterol metabolism, and inflammation in human brain cells, offering potential insights into the development and treatment of Alzheimer’s disease.
Alzheimer’s disease, the most prevalent form of dementia, has seen a rise in its prevalence over the years, posing significant challenges to the healthcare system and quality of life for affected individuals. The disease’s impact extends beyond memory loss, affecting one’s ability to work, financial planning for retirement, and overall well-being. Finding an effective treatment for Alzheimer’s disease is crucial for improving the quality of life for those affected by this condition.
Previous research has pointed to the role of a protein called ABCA7 in Alzheimer’s disease. This protein has been implicated in the pathogenesis of the disease through various genetic and genomic investigations, animal models, brain imaging studies, and postmortem examinations. In particular, older individuals who had low ABCA7 protein levels in the brain were found to be at a greater risk of developing Alzheimer’s disease. However, many questions remain about how ABCA7 functions, particularly its involvement in cholesterol metabolism and inflammation.
“Our goal is to extend human productive life by finding a way to prevent Alzheimer’s disease,” said study author Nicholas Lyssenko, an investigator at the Alzheimer’s Center at Temple and corresponding author on the new study. “A type of investigation called genome-wide association study (GWAS) has been conducted in human cohorts with Alzheimer’s disease over the past decade and a half. GWAS find tiny changes in the human genome that are over- or under-represented among those who have a disease. And that’s it. But these tiny changes are like one end of a string that can lead to a true cause of the disease at the other end.”
“Other types of investigation then ‘grab on’ to the end of the string and follow it to determine where it leads. A group of such tiny changes pointed to ABCA7 as a protein that affects whether an individual will develop Alzheimer’s. We began working on ABCA7 at that point and found that individuals with low levels of this protein in the brain experience onset of AD pathology in their 60s-70s.”
“We are now submitting to the journals follow-up results that further support those conclusions. Once we found out that low levels of this protein are detrimental to good cognitive health, we wondered what would bring this protein down. The report in Cells addresses some common situations, such as inflammation and a change in cholesterol levels.”
In the current study, Lyssenko and his colleagues conducted a series of experiments using different human brain cell lines, including microglia, astrocytes, and neurons. They aimed to understand how cholesterol metabolism and inflammation influence ABCA7 levels in these cells, potentially shedding light on Alzheimer’s disease development.
The scientists depleted cholesterol in these cell lines and then treated them with rosuvastatin, a medication that suppresses cholesterol synthesis. Additionally, they examined the impact of inflammation on ABCA7 by treating the cell lines with three proinflammatory cytokines: IL-1β, IL-6, and TNFα, which are small molecules that can trigger inflammation when secreted by certain immune cells.
The researchers found that ABCA7 levels decreased by approximately 40% in microglia cell lines and about 20% in an astrocyte cell line after cholesterol depletion. However, no changes were observed in ABCA7 levels in a neuronal cell line following cholesterol loss.
Inflammation, as induced by the proinflammatory cytokines IL-1β and TNFα, suppressed ABCA7 expression, but this effect was observed only in microglial cells. IL-6, another cytokine, had no impact on ABCA7 in microglia, and none of the three cytokines induced changes in ABCA7 levels in astrocytes or neurons.
These findings provide crucial insights into how ABCA7 is regulated in the human brain. The researchers suggest that cholesterol loss could downregulate ABCA7 in various brain cells, potentially contributing to the onset of Alzheimer’s disease. Additionally, this study revealed that inflammation may suppress ABCA7, both in astrocytes and microglia, further complicating the relationship between this protein, cholesterol metabolism, and inflammation in Alzheimer’s disease.
So should people worry about lowering their cholesterol levels? Lyssenko doesn’t think so. “Staying healthy and free of inflammation will not hurt your cognitive health or raise your risk of developing Alzheimer’s,” he explained to PsyPost. “I don’t want to overhype our results. But I want to ask the readers to stay tuned and follow our work. We work hard and expect new useful findings.”
ABCA7’s role appears to be a crucial factor in maintaining lipid balance (lipidostasis) in the brain. It may remove potentially neurodegenerative lipids from neural cells during normal physiological activities. The loss of ABCA7 during Alzheimer’s disease progression may result from sudden changes in inflammation or cholesterol metabolism.
“I expected that inflammation would raise ABCA7 levels, but it actually suppressed them,” Lyssenko told PsyPost. “But I work mostly in lipids and not inflammation. We then drew on the ideas of Dr. Ruslan Medzhitov (who we cite in the manuscript) about inflammation, and the result made sense.”
The findings provide important new insights, but it’s important to acknowledge the limitations of this study. The research primarily relied on in vitro experiments using cell lines, which may not fully represent the complex environment of the human brain. Additionally, the study focused on a specific aspect of ABCA7 regulation, and further research is needed to explore the broader context of its functions in Alzheimer’s disease.
Future research could investigate how changes in ABCA7 levels relate to the onset and progression of Alzheimer’s disease in human subjects. Understanding the role of ABCA7 in the disease’s pathogenesis could pave the way for developing targeted therapies that address the cholesterol metabolism and inflammation pathways, potentially offering new hope for Alzheimer’s patients.
“The challenge that has stumped us for some time is how to measure ABCA7 in the brain of living people,” Lyssenko said. “If we could do that (and we are working on this), then we would just recruit individuals with inflammation and measure ABCA7 and then know for sure that in people inflammation is bad for ABCA7. Right now, our results do not come from people.”
“I would like to draw the readers’ attention to the Alzheimer’s Center at Temple,” he added. “This is a relatively new and vibrant research unit that needs your support.”
The study, “Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA“, was authored by by Joel P. Wiener, Sindy Desire, Viktor Garliyev, Nicholas Lyssenko III, Domenico Praticò, and Nicholas N. Lyssenko.