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Pathway discovered that prevents Alzheimer's protein build-up



  Pathway Discovered That Prevents Building Alzheimer's Protein
First Author Bradlee Heckmann, Ph.D. (right), a postdoctoral fellow in Doug Green's (left) laboratory in St. Jude, led research that identified the LANDO pathway in the brain's immune cells and showed it could protect against Alzheimer's disease. Credit: St. Jude Children's Research Hospital

St. Jude Children's Research Hospital Researchers have discovered a pathway that acts as a car wash to prevent the build-up of a toxic protein associated with Alzheimer's disease. The report came online today in the journal Cell .

The results in a mouse model of Alzheimer's offer a possible new approach to treating the chronic neurodegenerative disorder, which is the sixth leading cause of death in the United States. The newly identified pathway also helps regulate inflammation, so the discovery can provide strategies for releasing the immune response to malignant brain tumors.

Scientists called the road LC3-associated endocytosis or LANDO. They found the way in microgial cells, the primary immune cells of the brain and central nervous system. However, preliminary evidence indicates LANDO is a basic process that works in cells throughout the body.

Investigators showed that LANDO protected against the occurrence of neurotoxic β-amyloid protein in mice. Activation of the road also protected against toxic neuroinflammation and neurodegeneration, including memory problems. "In the context of neurodegenerative diseases such as Alzheimer's, activation of LANDO in microgial cells may prove to be therapeutically beneficial in increasing clearance of β-amyloid and mitigation of neuroinflammation," says equivalent author Douglas Green, Ph.D. . Jude Immunological Department.

While activation of LANDO appears to protect against neurodegenerative disease, first author Bradlee Heckmann, Ph.D. Postdoctoral Researcher in Green's Laboratory said inhibition of the pathway may increase the effectiveness of cancer immunotherapy. "Although preliminary data using a primary brain tumor model suggests that inhibition of LANDO may provide a mechanism for activating inflammation within the tumor microenvironment to generate an antitumor response," Heckmann says.

Car wash β-amyloid protein accumulation in neurons is a hallmark of Alzheimer's. Scientists knew that microglial cells took up β-amyloid proteins. The discovery of the LANDO track answers questions about what's coming next.

Heckmann compared LANDO with the operator of an automatic car wash. In this case, the cars are receptors on the microgial cells that bind to neurotoxic β-amyloid proteins and bring the protein into the car wash. And just as cars return to the street after dirt is gone when β-amyloid is disposed of, the receptor returns to the microgial surface where it can pick up additional β-amyloid.

An automatic car wash depends on hardware to attach the car to a track that moves it through the machine. Similarly, more proteins are required for LANDO function. The Rubicon, Beclin 1

, ATG5 and ATG7 proteins are better known for their roles in a related cell pathway used to recycle unnecessary and unwanted cellular components. These proteins fall with age as their expression falls.

Follow the data

"You never know where science will lead," Green said. "This project started because we were studying immune responses to cancer. Brad acknowledged that the results were relevant to a disease, not to children, but to older people.

" How science works. When you follow the data, you never know where it will lead. "


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More Information:
Cell (2019). DOI: 10,1016 / j. Cell.2019.05.056

Journal information:
Cell

Provided by
St. Jewish Child Research Hospital

Citation :
Pathway Discovered That Prevents Building Alzheimer's Protein (2019, June 27)
June 27, 2019
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