A new study provides a missing link between inflammation and protein deposits that contribute to Alzheimer’s disease, according to findings published in Nature.
These findings will help future investigation of underlying mechanisms and treatments for Alzheimer’s disease, according to Robert Vassar, PhD, the Davee Professor of Alzheimer Research and a co-author of the study.
“The discovery of IFITM3 brings us closer to a more complete understanding of how inflammation sets the stage for Alzheimer’s disease,” said Vassar, who is also scientific director of Behavioral Neurology in the Ken & Ruth Davee Department of Neurology, a professor of Cell and Developmental Biology and director of the Alzheimer’s Disease Center P30 grant in the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease.
Amyloid-beta fragments are believed to be one of the main causes of Alzheimer’s disease, accumulating in the brain and leading to brain cell death. The normal function of amyloid-beta and the process that leads to its buildup are not well understood, according to the study authors.
Production of amyloid-beta is known to be controlled by the g-secretase enzyme complex, a protease complex that also regulates a variety of other mechanisms. Inhibiting the complex’s production of amyloid-beta while preserving other functions has been studied as an emerging therapeutic strategy. However, identifying the proteins that modulate amyloid-beta production alone has been difficult, according to the authors.
In the current study, investigators conduced an unbiased screening to search for proteins interacting with the g-secretase complex, eventually identifying interferon-induced transmembrane protein 3 (IFITM3).
They then ran a series of experiments to determine IFITM3’s precise function. When the investigators deleted IFITM3 from human stem cells, they found it reduced production of amyloid-beta, but did not affect levels of the g-secretase complex.
In addition, the scientists measured expression of IFITM3 in healthy mice, finding amounts of the protein significantly increased as the mice aged. IFITM3 was also upregulated in tissue samples of people with late-stage Alzheimer’s disease, indicating that at least part of the age-related increase in g-secretase activity and amyloid production is due to IFITM3.
IFITM3 is known to be upregulated with inflammation, so investigators treated mouse neurons with an inflammatory molecule, finding that the inflammation led to increased expression of IFITM3 and subsequently higher levels of amyloid-beta.
These findings shed new light on the role of inflammation in Alzheimer’s disease, providing a plausible pathway as well as a potential biomarker or therapeutic target for the condition.
“Our study suggests that anti-inflammatory drugs that cross the blood-brain barrier may lower IFITM3 levels and reduce amyloid-beta production, which should delay the onset and progression of Alzheimer’s disease,” Vassar said.
This work is supported by the JPB Foundation, the Fisher Center for Alzheimer’s Research Foundation, the Cure Alzheimer’s Fund, and the National Institutes of Health grants R01NS096275, RF1AG057593, R01AG061350, R01AG046170, RF1AG057440 and R01AG057907.
