Protein That Could Help Defeat Alzheimer’s

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. 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.

Previous work led by Nicholas Lyssenko, PhD, 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. 

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.”

Sources:

Joel P. Wiener, Sindy Desire, Viktor Garliyev, Nicholas Lyssenko III, Domenico Praticò, Nicholas N. Lyssenko. Down-Regulation of ABCA7 in Human Microglia, Astrocyte and THP-1 Cell Lines by Cholesterol Depletion, IL-1β and TNFα, or PMA. Cells, 2023; 12 (17): 2143 DOI: 10.3390/cells12172143

Temple University Health System. (2023, October 5). Protein that could help defeat Alzheimer’s and increase productive lifespan. ScienceDaily. Retrieved October 6, 2023 from www.sciencedaily.com/releases/2023/10/231005173755.htm

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