Research Briefs, Science & Technology

Neuroinflammation found to drive Alzheimer’s disease progression

Over a century ago, Alois Alzheimer, a German psychiatrist, spotted strange plaques and tangles in the brain slides of a patient with dementia. Ever since, scientists have been trying to better understand the mechanisms behind what is now known as Alzheimer’s disease.

Alzheimer’s disease (AD) is a brain disorder that progressively deteriorates cognitive and memory skills, eventually taking away the ability to perform even the most basic tasks, such as walking and eating. It is the most common cause of dementia among older adults and affects an estimated one in 10 people aged 65 or older.

From a biological standpoint, the disease is characterized by the accumulation of misfolded proteins, called amyloid beta, in the brain. They aggregate and form plaques that eventually trigger an inflammatory response. Microglia, the brain’s resident immune cells, activate and release molecules that cause further damage to the neurons. Another class of proteins, known as tau proteins, also get modified and clump together, forming tau tangles. The misfolded proteins then propagate according to hierarchical stages known as Braak stages. They originate from lower brain areas and make their way up to higher areas that control thinking and memory. The combination of amyloid plaques and tau tangles, along with the inflammatory response in the brain, is what scientists believe to be the physical basis of AD.

The role of brain tissue inflammation in Alzheimer’s, however, is still disputed among scientists.

“Some scientists believe that neuroinflammation can protect the brain because it would attack the amyloid plaques,” Dr. Pedro Rosa-Neto, director of the McGill Research Centre for Studies in Aging and professor of neurology and neurosurgery, said in an interview with The McGill Tribune.

Nevertheless, a recent McGill study has proven the alternative theory to be true: Neuroinflammation was found to drive the progression of the disease. The research team, led by Rosa-Neto, used an imaging technique called positron-emission tomography to quantify microglial activation, amyloid beta deposits, and tau propagation across the brain.

Their findings suggest that neuroinflammation is a precursor that allows tau proteins to spread to higher brain areas. 

“Microglial activation paves the way for tau to invade the brain,” Rosa-Neto said. 

The researchers also found that amyloid beta enhances the effect of microglial activation on tau proteins spreading through the brain. Their model shows that the combination of amyloid beta and microglial activation is what determines tau pathology.

This study clearly has considerable clinical applications; for instance, treating patients with anti-inflammatory drugs could prevent further progression of the disease. However, the clinical trials have been unsuccessful so far. There are many reasons for this failure, but an important one is that patients receiving the drugs are already in the late stages of the disease.

“The results that we found suggest that there is a right timing to give this medication, which is right at the beginning of the disease,” Rosa-Neto said. 

Indeed, neuroinflammation creates a path for the progression of misfolded tau proteins from lower to higher brain areas. Turning off neuroinflammation when misfolded tau are still confined within lower structures could prevent them from spreading further. Stopping neuroinflammation only when tau has already reached higher structures would likely be futile. 

As is the case for most complex diseases like Alzheimer’s, a lot of work needs to be done before scientists can reach a complete and accurate understanding of the disease mechanism. A clearer picture of how AD progresses is a promising start in ensuring better outcomes for patients. 

Last Tuesday, on World Alzheimer’s Day, Alzheimer’s Disease International released the World Alzheimer’s Report 2021—a comprehensive report of recent advances in the field. The 2021 report was entirely written by four McGill researchers, including Rosa-Neto, underscoring their standing as global leaders in Alzheimer’s research. 

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