Progranulin Contributes to Alzheimer’s Disease and Frontotemporal Dementia

Another protein was recently identified as being involved in Alzheimer’s disease by researchers at the Gladstone Institutes in California. Progranulin, a protein in the brain, can lead to amyloid-beta plaque formation when its levels are depleted.

“This is the first study providing evidence for a protective role of progranulin in Alzheimer’s disease,” said S. Sakura Minami, PhD, first author of the article describing the research, in a news release from Gladstone. “Prior research had shown a link between Alzheimer’s and progranulin, but the nature of the association was unclear. Our study demonstrates that progranulin deficiency may promote Alzheimer’s disease, with decreased levels rendering the brain vulnerable to amyloid-beta toxicity.”

To investigate the prior finding that progranulin is elevated in regions of plaque deposits in the brain and test the theory that progranulin is secreted in an attempt to counteract neurodegeneration, the team at Gladstone studied mouse models of Alzheimer’s disease. Described in “Progranulin Protects Against Amyloid Beta Deposition and Toxicity in Alzheimer’s Disease Mouse Models,” published in the journal Nature Medicine, the team manipulated the levels of progranulin produced by the mice and observed the effects on markers of inflammation.

Amyloid-beta plaque deposits and memory impairment increased with a decrease in progranulin. The immune system was stimulated to over-respond in the brain, potentially fueling neurological disorders in the mice. Conversely, an increase in progranulin led to lower levels of amyloid beta and a reversal of cognitive defects in the Alzheimer’s-induced mice.

Progranulin’s involvement in Alzheimer’s disease was attributed to its role in phagocytosis. Progranulin depletion impairs phagocytosis, allowing debris, dead cells, and amyloid-beta plaques to accumulate. Although the study did not address any pharmaceutical means to increase progranulin, it may be an interesting avenue of research to translate the findings of the study into the clinic.

Alzheimer’s is not the only disease now associated with progranulin. Frontotemporal dementia, a neurodegenerative disorder similar to Alzheimer’s, is caused by low levels of progranulin. However, frontotemporal dementia shows signs of greater injury to the frontal cortex, which leads to changes in behavior and personality, whereas Alzheimer’s damages memory centers of the hippocampus and temporal cortex.

“The next step will be to develop progranulin-enhancing approaches that can be used as potential novel treatments, not only for frontotemporal dementia, but also for Alzheimer’s disease,” concluded Li Gan, PhD, senior author of the paper.