Researchers at Washington University School of Medicine in St. Louis explored the structure of a molecule that is thought to play a key role in Alzheimer's disease.

Role Of TREM2 In Neurodegenerative Diseases

Scientists believe that a molecule named TREM2 is responsible for causing cognitive decline, a prime symptom of neurodegenerative diseases. It was explained in previous studies that mutation in TREM2 could elevate the risk of late-onset Alzheimer's, Parkinson's disease, frontal temporal dementia and sporadic amyotrophic lateral sclerosis.

In addition, mutation in TREM2 is also associated with Nasu-Hakola disease, a genetic disease that causes dementia in adulthood and results in death at as early as 50 years.

Thomas J. Brett, an assistant professor at WUSM, said that while it is unclear how the defective TREM2 causes degeneration in brain, it is quite certain that inflammation could be the reason behind all such ailments.

Analysis Of Structure Of TREM2

The current study is focused on the mutations caused in TREM2; the changes in the protein structure as a result of mutation; and how it affects the function of the molecule, noted Brett. The researcher also added that a clear understanding on these issues would help in developing effective treatment options.

As far as Alzheimer's disease is concerned, the mutation is found to alter the protein surface, whereas in Nasu-Hakola, the mutation alters the "gut" of the protein, noted Daniel L. Kober, the study's first author, who analyzed the structure of TREM2. It is understandable from the site of mutation why Nasu-Hakola is far severe than Alzheimer's disease.

TREM2 And Alzheimer's Disease

The mutation caused in the gut of the protein disrupts the molecule completely and results in fewer TREM2, which could be attributed to onset of dementia in early adulthood in Nasu-Hakola. Meanwhile, in case of Alzheimer's, while the structure of TREM2 remains intact, its functions are impaired. The mutation makes it difficult for the TREM2 to connect to proteins and pass signals as in healthy molecules.

TREM2 is present on the surface of the microglia, the immune cells responsible for cleaning up the cellular waste including beta amyloid that pile up in Alzheimer's through a process called phagocytosis. The "housekeeping" process of microglia is disturbed when the TREM2 are scarce or dysfunctional.

"Exactly what TREM2 does is still an open question," said Brett. "We know mice without TREM2 have defects in microglia, which are important in maintaining healthy brain biology."

TREM2 is also associated with many inflammatory conditions such as stroke and chronic obstructive pulmonary disease, therefore understanding TREM2's structure would help in the intervention of various degenerative and chronic diseases.

The study is published in the journal eLife.

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