Posted on Oct 06, 2023, 5 p.m.
Alzheimer's disease is the most common type of dementia, a disorder of progressively worsening memory and other thinking abilities. It rose up in the ranks of leading causes of death over the past several decades. It can also limit the duration of a working career, create uncertainty in the financial planning for retirement and rob patients of enjoyment and happiness in the final years. An effective treatment against this disease could give back to the patient the decision when to retire and improve quality of life in advanced age.
Now, scientists at the Alzheimer's Center at Temple at the Lewis Katz School of Medicine at Temple University are on the trail of a promising new therapeutic target -- ABCA7, a protein known to protect from Alzheimer's disease. The study, published online in the journal Cells, uncovers new information about the relationship between ABCA7, cholesterol, and inflammation in human brain cells.
The importance of ABCA7 in the development of Alzheimer's disease first emerged in genome-wide association studies, which are large investigations of the human genome that involve 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," said Joel Wiener, an investigator with the Alzheimer's Center at Temple and first author on the new report. "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."
Previous work led by Nicholas Lyssenko, PhD, an investigator at the Alzheimer's Center at Temple and corresponding author on the new study, suggested that individuals between ages 63 and 78 who have low ABCA7 protein levels in the brain are at a greater risk of developing Alzheimer's disease. This finding corroborated the conclusions of earlier genome studies and further indicated that the protein protects the human brain.
In the new study, Dr. Lyssenko's team addressed how cholesterol metabolism and inflammation may manipulate ABCA7 levels in human brain cells and thus affect Alzheimer's disease pathogenesis. In one set of experiments, the researchers depleted cholesterol in different neural cell lines, such as microglia, astrocytes and neurons, and then treated the cells with rosuvastatin, a medication that suppresses cholesterol synthesis. To determine the effect of inflammation on ABCA7, the team carried out another set of experiments in which the same cell lines were treated with one of three major proinflammatory cytokines: IL-1β, IL-6, or TNFα. Cytokines are small molecules that can trigger inflammation following their secretion from certain types of immune cells.
The researchers found that ABCA7 levels dropped by about 40 percent in microglia cell lines and about 20 percent in an astrocyte cell line after the cells were depleted of more than half their usual amount of cholesterol. Meanwhile, no changes were observed in ABCA7 levels in a neuronal cell line following cholesterol loss. In addition, IL-1β and TNFα suppressed ABCA7 expression only in microglial cells. The third cytokine, IL-6, had no impact on ABCA7 in microglia, and none of the three cytokines induced changes in ABCA7 levels in either astrocytes or neurons.
These observations advance 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," said Mr. Wiener. "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."
The Temple team is taking multiple approaches to studying ABCA7, using not only human cells but also carrying out experiments in animal models and in 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 added. "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."
Other researchers who contributed to the study include Sindy Desire, Viktor Garliyev, Nicholas Lyssenko III, and Domenico Praticò, Alzheimer's Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine.
The research was supported by funding from the National Institute on Aging at the National Institutes of Health (NIH) and from the Pennsylvania Department of Health, Commonwealth Universal Research Enhancement Program.
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This article was written at the Temple University Health System