Neuroinflammation and Neurodegeneration May Go Hand in Hand
Does neuroinflammation trigger a chain reaction that increases Alzheimer's risk?
Posted Sep 03, 2020
Alzheimer's disease is characterized by the build-up of beta-amyloid plaques that clump together in the brain. Although these clumps of beta-amyloid protein are a defining, signature feature of Alzheimer's disease, until recently, scientists have had difficulty pinpointing the exact mechanisms that cause the clumping of these Aβ plaques.
Identifying what causes the accumulation of beta-amyloid plaques has been like a holy grail for researchers around the world; scientists have been searching for new and better ways to prevent cognitive decline in aging populations and offset people's risk of developing Alzheimer's disease. (Whether beta-amyloid build-up is a main cause or just a feature of the disease has been debated.)
A growing body of evidence suggests that inflammatory cytokines may trigger a chain reaction that increases the production and accumulation of toxic proteins that lead to beta-amyloid plaque build-up and subsequent neurodegeneration.
This week, a research team announced that they've discovered how the immune system's inflammatory response may play a role in the development of Alzheimer's disease. These groundbreaking findings (Hur et al., 2020) on how an innate immunity protein called IFITM3 modulates gamma-secretase in Alzheimer's disease were published on September 2 in the journal Nature.
According to the authors, this is the first study to identify a direct link between IFITM3-related neuroinflammation and Aβ plaque production. The study suggests that viral and bacterial infections may play a role in the formation of amyloid-plaque clumps.
Previous research has established that harmful invaders such as a virus or bacteria that trigger an immune system response kickstart the production of IFITM3. The researchers speculate that IFITM3—which is widely recognized as a key player in how the immune system responds to harmful invaders (i.e., pathogens) by triggering inflammation—may also be part of a previously unrecognized mechanism that modulates gamma-secretase activity in a way that could increase Alzheimer's disease risk.
"We've known that the immune system plays a role in Alzheimer's disease—for example, it helps to clean up beta-amyloid plaques in the brain," senior author Yueming Li of Memorial Sloan Kettering Cancer Center said in a news release. "But this is the first direct evidence that immune response contributes to the production of beta-amyloid plaques—the defining feature of Alzheimer's disease."
Using a mouse model, a team of researchers led by Ji-Yeun Hur and Georgia R. Frost found that inflammatory cytokines trigger the expression of IFITM3 proteins in a way that upregulates gamma-secretase activity—which subsequently increases the production of amyloid-β.
Conversely, the researchers found that removing IFITM3 in knockout mice decreased gamma-secretase enzyme activity, which reduced the accumulation of beta-amyloid plaques in an Alzheimer's disease mouse model. Li and his Sloan Kettering colleagues also found a correlation between IFITM3 levels, gamma-secretase activity, and beta-amyloid build-up in human brain samples.
"The amount of IFITM3 in the gamma-secretase complex has a strong and positive correlation with gamma-secretase activity in samples from patients with late-onset Alzheimer's disease," the authors noted. "These findings reveal a mechanism in which gamma-secretase is modulated by neuroinflammation via IFITM3, and the risk of Alzheimer's disease is thereby increased."
For their next phase of research into how inflammation is linked to Alzheimer's disease, Yueming Li's Lab will investigate how IFITM3 interacts with gamma-secretase at the molecular and atomic levels. They're also planning to explore how to use IFITM3 as a biomarker to test for Alzheimer's disease development and as a potential target for drug treatments.
Ji-Yeun Hur, Georgia R. Frost, Xianzhong Wu, Christina Crump, Si Jia Pan, Eitan Wong, Marilia Barros, Thomas Li, Pengju Nie, Yujia Zhai, Jen Chyong Wang, Julia TCW, Lei Guo, Andrew McKenzie, Chen Ming, Xianxiao Zhou, Minghui Wang, Yotam Sagi, Alan E. Renton, Bianca T. Esposito, Yong Kim, Katherine R. Sadleir, Ivy Trinh, Robert A. Rissman, Robert Vassar, Bin Zhang, Douglas S. Johnson, Eliezer Masliah, Paul Greengard, Alison Goate & Yue-Ming Li. "The Innate Immunity Protein IFITM3 Modulates γ-Secretase in Alzheimer’s Disease." Nature (First published: September 02, 2020) DOI: 10.1038/s41586-020-2681-2