CFR Researchers Report Progranulin Protects Against Alzheimer Disease

SAN FRANCISCO, CA 10/26/14 - Researchers in the laboratory of CFR Investigator Li Gan, PhD at the Gladstone Institutes recently reported that mice genetically modified to develop Alzheimer’s disease faired worse if they also lacked progranulin. Their work, which was co-authored with scientists in the labs of CFR Investigator Bob Farese, MD, and CFR Internal Advisory Board member Lennart Mucke, MD, was published online in Nature Medicine on September 28, 2014.

Mutations in the gene progranulin ultimately cause FTD, but the exact pathophysiology remains unclear. Previous work from CFR researchers demonstrated that specific immune cells in the brain, called microglia, are hyperactivated if they lack progranulin, suggesting progranulin may moderate inflammation. Dr. Gan’s group decided to use Alzheimer’s disease (AD), which produces an inflammatory state in the brain, as a model in which to investigate progranulin’s anti-inflammatory effect.

“Because progranulin is such an important anti-inflammatory factor, we wondered whether it was effective in preventing some of the pathological hallmarks of AD,” said first author S. Sakura Minami, PhD.

Led by Dr. Minami, PhD, the researchers found that mice with AD performed worse on memory tests and showed elevated neuronal death if they lacked progranulin. The findings support previous human epidemiologic studies that linked low progranulin levels with an elevated risk of developing AD. Importantly, when the researchers reintroduced progranulin, by injecting it into the brains of affected mice, these defects disappeared.

To look at progranulin’s function specifically in microglia, they produced animals that had reduced levels of progranulin in microglia but normal levels in other cell types. The researchers found that a key hallmark of AD, the appearance of insoluble plaques containing a protein called A-beta, was greatly elevated in brains of animals with low microglial progranulin. Microglia phagocytose, or “clean-up,” cellular debris such as plaques, thus the increased plaque load in these animals suggested their microglia may be defective. Indeed, Dr. Minami and colleagues showed that microglia with reduced progranulin were far less efficient at internalizing fluorescent beads than normal microglia.

“This finding, that reduced progranulin directly affects the presence of Abeta plaques, was unexpected. We initially assumed an indirect protective effect through downstream anti-inflammatory processes, but our data instead revealed a direct effect on Abeta through microglial dysfunction,” said Dr. Minami. She plans to further investigate the mechanism by which progranulin is neuroprotective with a particular focus on which signaling pathways underlie the microglial defect in phagocytosis.

These results suggests progranulin has a protective role against the development of AD, therefore therapeutics that raise progranulin levels for the treatment of progranulin-deficient FTD may also be beneficial for the treatment of AD. Given the key role of microglia in modulating neuroinflammation, progranulin-elevating drugs may have a broader role in treating other neurodegenerative diseases as well.

This study, entitled “Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models” was partially funded by the Consortium for FTD Research.