Inflammation linked to Alzheimer's disease development

Date:
September 2, 2020
Source:
Memorial Sloan Kettering Cancer Center
Summary:
Scientists have discovered a direct link between the immune
response to viruses and bacteria and the development of plaques
in the brain that characterize Alzheimer's disease.



FULL STORY ========================================================================== Alzheimer's disease is a neurodegenerative condition that is characterized
by the buildup of clumps of beta-amyloid protein in the brain. Exactly
what causes these clumps, known as plaques, and what role they play in
disease progression is an active area of research important for developing prevention and treatment strategies.


========================================================================== Recent studies have found that beta-amyloid has antiviral and
antimicrobial properties, suggesting a possible link between the immune response against infections and the development of Alzheimer's disease.

Chemical biologists at the Sloan Kettering Institute have now discovered
clear evidence of this link: A protein called IFITM3 that is involved in
the immune response to pathogens also plays a key role in the accumulation
of beta-amyloid in plaques.

"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,"
says Yue-Ming Li, a chemical biologist at SKI. "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."
In a paper published September 2 in Nature, Dr. Li and his team show
that IFITM3 alters the activity of an enzyme called gamma-secretase,
which chops up precursor proteins into the fragments of beta-amyloid
that make up plaques.

They found that removing IFITM3 decreased the activity of the
gamma-secretase enzyme and, as a result, reduced that number of amyloid
plaques that formed in a mouse model of the disease.

Mounting Evidence for a New Hypothesis Neuroinflammation, or inflammation
in the brain, has emerged as an important line of inquiry in Alzheimer's disease research. Markers of inflammation, such as certain immune
molecules called cytokines, are boosted in Alzheimer's disease mouse
models and in the brains of people with Alzheimer's disease. Dr.

Li's study is the first to provide a direct link between this inflammation
and plaque development -- by way of IFITM3.

Scientists know that the production of IFITM3 starts in response to
activation of the immune system by invading viruses and bacteria. These observations, combined with the new findings from Dr. Li's lab that
IFITM3 directly contributes to plaque formation, suggest that viral
and bacterial infections could increase the risk of Alzheimer's disease development. Indeed, Dr. Li and his colleagues found that the level of
IFITM3 in human brain samples correlated with levels of certain viral infections as well as with gamma-secretase activity and beta-amyloid production.

Age is the number one risk factor for Alzheimer's, and the levels of both inflammatory markers and IFITM3 increased with advancing age in mice,
the researchers found.

They also discovered that IFITM3 is increased in a subset of late onset Alzheimer's patients, meaning that IFITM3 could potentially be used
as a biomarker to identify a subset of patients who might benefit from therapies targeted against IFITM3.

The researchers next plan is to investigate how IFITM3 interacts with
gamma- secretase at the molecular and atomic levels and how it is
involved in neuroinflammation in animal models. They will also explore
IFITM3 as a biomarker for the disease and as a potential target for new
drugs designed to treat it.


========================================================================== Story Source: Materials provided by
Memorial_Sloan_Kettering_Cancer_Center. Original written by Matthew
Tontonoz. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Hur, J., Frost, G.R., Wu, X. et al. The innate immunity protein
IFITM3
modulates g-secretase in Alzheimer's disease. Nature, 2020 DOI:
10.1038/ s41586-020-2681-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200902114455.htm

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