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Sep 29, 2014 12:05 PM EDT

Gene Therapy Could Protect Against Dementia, Alzheimer's Disease

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A protein occurring protein that exacerbates cellular and cognitive dysfunction is also implicated in Alzheimer's disease, according to a recent study.

Researchers at the Gladstone Institutes have found that low levels of the protein progranulin in the brain can increase the formation of amyloid-beta plaques (a hallmark of Alzheimer's disease), cause neuroinflammation, and worsen memory deficits in a mouse model of this condition.  Conversely, by using a gene therapy approach to elevate progranulin levels, scientists were able to prevent these abnormalities and block cell death in this model.

Progranulin deficiency is known to cause another neurodegenerative disorder, frontotemporal dementia (FTD), but its role in Alzheimer's disease was previously unclear. Although the two conditions are similar, FTD is associated with greater injury to cells in the frontal cortex, causing behavioral and personality changes, whereas Alzheimer's disease predominantly affects memory centers in the hippocampus and temporal cortex.

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

For the study, researchers manipulated several different mouse models of Alzheimer's disease, genetically raising or lowering their progranulin levels.

They found that reducing progranulin markedly increased amyloid-beta plaque deposits in the brain as well as memory impairments. It also triggered "an over-active immune response" in the brain, which can contribute to neurological disorders, researchers said.

In contrast, increasing progranulin levels via gene therapy effectively lowered amyloid beta levels, protecting against cell toxicity and reversing the cognitive deficits typically seen in these Alzheimer's models.

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

The findings were published in Nature Medicine.

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