New Insights into Alzheimer’s Disease from Misfolded Proteins

Researchers have identified a new group of proteins in the brain that might significantly contribute to the onset and progression of Alzheimer’s disease.

Traditionally, the focus has been on amyloid and tau proteins, which were believed to be the primary factors causing the serious cognitive decline associated with Alzheimer’s.

However, a recent investigation led by Johns Hopkins University has revealed over 200 additional misfolded proteins in rats that may negatively impact brain function and speed up memory loss.

Misfolded proteins are those that haven’t assumed their correct three-dimensional structure.

The study suggests these hidden proteins do not aggregate into large clumps like amyloids, which makes them more challenging to detect. Researchers suspect these improperly formed proteins could disrupt normal brain operations.

‘Amyloids are big and easy to spot under a microscope, so they’ve attracted much of the attention,’ noted lead researcher Dr. Stephen Fried. ‘But our findings indicate they’re just the tip of the iceberg.’

Alzheimer’s is the most prevalent form of dementia, mainly affecting individuals aged over 65.

Currently, more than 7.2 million adults in the US within this age group are living with Alzheimer’s, resulting in over 100,000 fatalities each year.

While the study was based on rats, Dr. Keith Vossel, a Neurology professor at UCLA, emphasizes the need for further research to explore if these misfolded proteins can cause Alzheimer’s in humans.

‘It’s a small step forward, but it certainly enhances our understanding of this disease,’ he mentioned.

To confirm if similar changes occur in human brains, Dr. Vossel explained, ‘would necessitate autopsy-based studies or examining removed hippocampal tissue — that’s really the only way to assess it directly.’

‘Right now, it’s an interesting association,’ he added, ‘but it requires a lot more follow-up.’

The findings may lead to new avenues for treatment and targets for Alzheimer’s, which currently has no cure.

The Alzheimer’s Association warns that by 2050, nearly 13 million Americans could be affected by the disease.

Typically, the disease is associated with the formation of amyloid plaques and tau tangles in the brain that damage and kill cells.

These plaques and tangles arise when amyloid proteins misfold and bond together, creating sticky clumps (plaques), and tau proteins become twisted (tangles). These toxic accumulations hinder neurons from sending signals efficiently.

Due to being misfolded, these proteins cannot perform essential cellular tasks, leading to damage.

Over time, this can impair brain function and cause memory and muscular decline, potentially resulting in permanent damage that precipitates Alzheimer’s.

As the disease progresses, individuals may lose the ability to communicate, manage daily tasks, or even interact with their surroundings.

To delve deeper into the molecular mechanisms at play, Dr. Stephen Fried and his team studied 17 rats, all aged two years and raised under similar conditions.

After conducting memory and problem-solving assessments, seven of the rats displayed notable cognitive impairments, despite being in the same environment as the other ten.

This allowed the researchers to investigate what might be occurring in the brains of the impaired rats, leading to the identification of over 200 potentially harmful proteins.

The other ten rats performed comparably to six-month-old rats on the same tests.

Scientists analyzed more than 2,500 protein types across all rats’ hippocampi, the brain area associated with spatial learning and memory.

They discovered over 200 proteins were misfolded in those with cognitive impairment, though it’s still unclear which specific proteins are involved.

Conversely, the same proteins remained properly formed in the cognitively healthy rats who had scores similar to their younger counterparts.

Consequently, the researchers concluded that these misfolded proteins likely contribute to cognitive decline.

‘We believe there are several proteins that can misfold, not form amyloids, yet still be problematic,’ Fried remarked regarding the findings.

Looking ahead, Fried and his team plan to further investigate these phenomena with high-resolution microscopes to enhance understanding of their deformities at a molecular level.

‘Many of us have seen a loved one struggle to handle everyday tasks that require cognitive skills,’ he said.

‘Understanding what’s physically happening in the brain could lead to improved treatments and preventive measures.’

The study was published on July 11 in the journal Science Advances.