Deteriorating neurons are source of human brain inflammation in Alzheimer’s disease

Despite decades of research, Alzheimer’s disease remains a debilitating and eventually fatal dementia with no effective treatment options. More than 95 percent of Alzheimer’s disease cases have no known origin. Now, scientists from the Salk Institute have found that neurons from people with Alzheimer’s disease show deterioration and undergo a late-life stress process called senescence. These neurons have a loss of functional activity, impaired metabolism, and increased brain inflammation.

The researchers also discovered that targeting the deteriorating neurons with therapeutics could be an effective strategy for preventing or treating Alzheimer’s disease. The findings were published online in Cell Stem Cell on December 1, 2022.

“Our study clearly demonstrates that these non-replicating cells are going through the deterioration process of senescence and that it is directly related to neuroinflammation and Alzheimer’s disease,” says co-corresponding author and Professor Rusty Gage, president of the Salk Institute and holder of the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.

As cells age, they can undergo cellular senescence, which contributes to tissue dysfunction and age-related disorders. Senescence is also thought to play a role in cellular stress, molecular damage, and cancer initiation. However, scientists previously believed that senescence primarily occurred in dividing cells, not in neurons. Little was known about the senescence-like state of aging human neurons.

In this study, Gage and his team took skin samples from people with Alzheimer’s disease and converted those cells directly into neurons in the lab. They tested these neurons to see if they undergo senescence and examined the mechanisms involved in the process. They also explored senescence markers and gene expression of post-mortem brains from 20 people with Alzheimer’s disease and matched healthy controls. This allowed the team to confirm that their results from the lab held true in actual human brain tissue.

The Gage team found that senescent neurons are a source of the late-life brain inflammation observed in Alzheimer’s disease. As the neurons deteriorate, they release inflammatory factors that trigger a cascade of brain inflammation and cause other brain cells to run haywire. Additionally, the gene KRAS, which is commonly involved in cancer, could activate the senescent response.

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