Scientists find over 200 hidden proteins that may drive Alzheimer’s: Study

In a groundbreaking discovery, scientists at Johns Hopkins University have identified over 200 previously undetected misfolded proteins in the brains of aging rats with cognitive decline—a finding that could revolutionize our understanding of Alzheimer’s disease and other neurodegenerative conditions.

Unlike the well-known amyloid-beta and tau proteins, these newly discovered misfolded proteins do not form visible aggregates, making them difficult to detect but potentially just as damaging to memory and cognition.

Silent Saboteurs: Proteins That Escape Brain’s Defense

“These are proteins that misfold without forming amyloids,” said Stephen Fried, assistant professor of chemistry and lead investigator of the study. “Amyloids are big and easy to spot under a microscope, but our research shows they’re just the tip of the iceberg.”

These “stealth” misfolded proteins appear to bypass the brain’s natural cleanup mechanisms, possibly leading to progressive cognitive damage over time. The discovery offers a new perspective on how brain degeneration may occur silently, even in the absence of visible plaques.

Study Overview: Rats, Memory Tests, and Molecular Clues

Published on July 11 in Science Advances, the study analyzed brain tissue from 17 two-year-old rats—the rodent equivalent of elderly humans. Seven of the rats displayed cognitive impairment, based on poor performance in spatial learning and memory tests, while the other ten performed at levels comparable to younger six-month-old rats.

Researchers examined over 2,500 proteins in the hippocampus, the brain region critical for memory. They found more than 200 proteins that were misfolded in cognitively impaired rats but maintained their normal structure in healthy ones—strongly suggesting a link between protein deformation and declining cognitive function.

Beyond Amyloids: A New Frontier in Dementia Research

Until now, amyloid-forming proteins like A-beta and tau were considered the main culprits in Alzheimer’s disease. But Fried and his team believe that many other misfolded proteins, although invisible to standard detection methods, could be just as harmful.

“We think there are a lot of misfolded proteins that don’t form amyloids and are still harmful,” Fried explained. “That suggests they have a way of escaping the cell’s surveillance system—but we don’t yet know how.”

Next Steps: Mapping the Invisible Threat

The team is now working with high-resolution microscopy to better understand the structure and behavior of these stealth misfolded proteins, aiming to uncover new therapeutic targets for early intervention and treatment.

“A lot of us have seen loved ones lose the ability to perform everyday tasks,” Fried added. “Understanding what’s physically happening in the brain could lead to better treatments and preventive approaches.”

This study opens the door to rethinking how we detect and treat Alzheimer’s and age-related cognitive decline—by focusing not just on what we can see, but also on the invisible molecular threats lurking in the aging brain.

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