For the first time, scientists have identified a rare population of potentially toxic senescent cells in human brains that can serve as a target for a new Alzheimer’s disease treatment.

The study was published in the journal Nature Aging.

Senescent cells are old, sick cells that cannot properly repair themselves and don’t die off when they should. Instead they function abnormally and release substances that kill surrounding healthy cells and cause inflammation. Over time, they continue to build up in tissues throughout the body contributing to the aging process, neurocognitive decline and cancer.

Research conducted in 2018 found that senescent cells accumulated in mouse models of Alzheimer's disease where they contributed to brain cell loss, inflammation and memory impairment. When the researchers used a therapy to clear the senescent cells, they halted disease progression and cell death.  

“However, until now, we didn’t know to what extent senescent cells accumulated in the human brain, and what they actually looked like,” the senior author said. “It was somewhat like looking for the proverbial needle in a haystack except we weren’t sure what the needle looked like.”

Using sophisticated statistical analyses, the research team was able to evaluate large amounts of data. In total, they profiled tens of thousands of cells from the postmortem brains of people who had died with Alzheimer’s disease. The researchers’ plan was to first determine if senescent cells were there, then how many there were and what types of cells they were. They succeeded.

The team found that approximately 2% of the brain cells were senescent and also identified the type of cell and the characteristic features.

The study findings indicated that the senescent cells were neurons, which are the fundamental units in the brain that process information and are the workhorses of memory. They also are the primary cells that are lost in Alzheimer's disease.

Next, the team sought to determine if the senescent neurons had tangles – abnormal accumulations of a protein called tau that can collect inside neurons in Alzheimer’s disease. These tangles closely correlate with disease severity, meaning that the more tangles individuals have in their brains, the worse their memory, the senior author said. 

The researchers found that the senescent neurons not only had tangles but that they overlapped to the point that it was hard to distinguish between them. 

Lastly, the team validated the findings by examining a different cohort of postmortem brain tissue samples from people with Alzheimer’s.

“Now that we have identified these cells in the brain, we have opened the door to many possibilities, including treatment options for people with Alzheimer's,” the senior author said.

The team are paving the way in senolytics research for Alzheimer’s disease, opening up a new target for potential treatments. This is especially exciting for the field as we now know we will need drugs that work against the many underlying biological processes that go wrong as we age – like the buildup of toxic senescent cells – that contribute to Alzheimer’s disease.

https://www.nature.com/articles/s43587-021-00142-3