IIT-Mandi team finds how protein clusters are formed in Alzheimer’s

Researchers at the Indian Institute of Technology (IIT) Mandi have discovered an important biomolecular mechanism for the formation of protein clusters or aggregates that are often seen in Alzheimer’s disease.

Alzheimer’s is the most common form of dementia that slowly destroys memory and other important mental functions.

The team, which also included researchers from the University of Cambridge, UK, and University of South Florida in the US, showed that signal peptide of the Amyloid Precursor Protein (APP) can combine with other peptides to form misfolded aggregates like Amyloid beta peptide that deposit outside of cells and cause diseases.

Signal peptides act as a postal address for the proteins inside the cell. While proteins are essential for virtually every process within the cell, their disturbed functions due to aggregation and/or misfolding can result in harmful effects. There are more than 50 diseases that are associated with protein aggregation/misfolding.

Alzheimer’s, for example, is linked with the deposition of misfolded peptides called Amyloid beta peptide in the spaces between nerve cells.

But till now, it was unknown that signal peptide of APP also have the tendency to form disease-causing aggregates.

“In Amyloid precursor protein, so far only Aß region was known to form toxic aggregates. Here, we discovered that Signal peptide of Amyloid precursor protein not only forms cell-killing aggregates but also enhances the aggregation of Amyloid beta peptide peptide, under in-vitro conditions,” said lead researcher Dr. Rajanish Giri, Associate Professor, at IIT-Mandi’s School of Basic Sciences.

In the study, published in the journal Cell Reports Physical Science, Giri noted that usually, as the protein reaches to its destination, the signal peptides are cut off from the proteins and often degraded by the cellular machinery.

To understand, the team studied the aggregation pattern of a signal peptide of the APP, which after being cut-off is called APP1-17SP.

They found that APP1-17SP associates with Alzheimer’s disease-associated peptide Amyloid beta peptide and forms aggregates with higher toxicity.

The team performed experiments on the APP1-17SP using dye-based assays and found that APP1-17SP can bind to these aggregate-tracking dyes. Similar experiments of APP1-17SP with Amyloid beta peptide peptide also led to the formation of characteristic fibrillar aggregates. In fact, the Amyloid beta peptide-APP1-17SP mixture displayed higher cytotoxicity compared with Amyloid beta peptide and APP1-17SP separately.

“This is the first report on an aggregation of signal peptides in isolation” said Giri. “Our study shows a possible link between signal peptide aggregation and Alzheimer’s Amyloid beta peptide peptide aggregation.”

“This study will help in future research that could provide relation of other signal peptides to disease pathogenesis,” he noted.



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