In healthy brains, immune cells called microglia patrol for damage, clearing away debris and harmful proteins. But in the presence of the APOE4 protein—the most important genetic risk factor for Alzheimer’s disease—the same cells cause harmful inflammation and clumps of misfolded proteins, according to a new study by scientists at Gladstone Institutes.

The team created a new research model for studying Alzheimer’s that involved transplanting human neurons producing the APOE4 protein into the brains of mice.

When they removed microglia from the brains, they discovered that the APOE4 protein no longer triggered as many deposits of amyloid or tau—two types of misfolded proteins that are hallmarks of Alzheimer’s disease.

“The study underscores the importance of microglia, in concert with APOE4 produced by human neurons, in Alzheimer’s,” says Gladstone Senior Investigator Yadong Huang, MD, PhD, who supervised the new study published in Cell Stem Cell. “Our findings suggest that drugs reducing microglia may eventually be useful in treating the disease.”

Insights Into How Brain Immune Cells Trigger Inflammation Offer New Avenues for Targeted Alzheimer's Therapies

There are three major forms of APOE protein in humans. Compared with the most common version of the protein—APOE3—the APOE4 protein increases risk and APOE2 decreases risk for Alzheimer’s disease.

About one in four Americans has at least one copy of the APOE4 gene, and roughly 3 percent have two copies, making those individuals especially susceptible to the disease.

“People with two copies of the APOE4 gene have a 12-fold greater risk of developing Alzheimer’s disease than those with APOE3,” says Huang, who is also director of the Center for Translational Advancement at Gladstone and a professor in the Departments of Neurology and Pathology at UC San Francisco.

To study the complex interplay between APOE variants and brain cells, Huang and his team have long relied on mouse models, just as many other research groups do. However, mimicking the human brain in a mouse is difficult; adding human genes for APOE4 to mice, as is often done, does not fully capture how human brain cells behave in Alzheimer’s disease.

Read the full article about brain immune cells by Sarah C. P. Williams at Gladstone Institutes.