Gene therapy reverses symptoms of Alzheimer’s associated with progranulin deficiency

Lower amounts of a protein called progranulin in the brain have been shown to increase beta-amyloid formation and neuroinflammation. A gene therapy may be the key to reversing these markers of Alzheimer’s disease, Gladstone Institutes announced yesterday.

S. Sakura Minami, PhD, a postdoctoral fellow at Gladstone Institutes, an independent non-profit biomedical research organization affiliated with the University of California, San Francisco, and colleagues were able to reduce levels of progranulin protein in preclinical mouse models and see the worsening of neurodegenerative and cognitive symptoms and then increase levels of the protein via gene therapy to see a reversal of these symptoms. The researchers believe that progranulin may be the brain’s way of reducing inflammation as a defense against disease.

Previous research implicated progranulin deficiency in frontotemporal dementia, but this is the first study that teases out the connection between progranulin and Alzheimer’s disease.

“This is the first study providing evidence for a protective role of progranulin in Alzheimer’s disease,” Minami said in a statement. “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.”

Progranulin deficiency not only led to symptoms of neuroinflammation and accumulation of amyloid, but it also prompted hyperactive immune response, which has been linked to worsening pathophysiology of neurodegenerative disease. Researchers developed a gene therapy that increases progranulin in the brain thereby preventing cell toxicity and death and improving cognition in Alzheimer’s models. Progranulin’s effect may be due to its relationship to phagocytosis, the body’s natural clean-up crew, which may be essential to reducing plaque build up.

"The profound protective effects of progranulin against both amyloid-beta deposits and cell toxicity have important therapeutic implications," said Li Gan, PhD, a senior author in the study. "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."