Senescent cells elimination prevents neurodegeneration

Zombie cells are the ones that can't die but are equally unable to perform the functions of a normal cell. These zombie, or senescent, cells are implicated in a number of age-related diseases. And with a new letter in Nature, researchers have expanded that list.

In a mouse model of brain disease, scientists report that senescent cells accumulate in certain brain areas prior to cognitive loss. By preventing the accumulation of these cells, they were able to diminish tau protein aggregation, neuronal death and memory loss.

"Senescent cells are known to accumulate with advancing natural age and at sites related to diseases of aging, including osteoarthritis; atherosclerosis; and neurodegenerative diseases, such as Alzheimer's and Parkinson's," says the senior author of the paper. "In prior studies, we have found that elimination of senescent cells from naturally aged mice extends their healthy life span."

In the current study, the team used a model that imitates aspects of Alzheimer's disease.

"We used a mouse model that produces sticky, cobweb like tangles of tau protein in neurons and has genetic modifications to allow for senescent cell elimination," explains first author. "When senescent cells were removed, we found that the diseased animals retained the ability to form memories, eliminated signs of inflammation, did not develop neurofibrillary tangles, and had maintained normal brain mass."

Authors found that the MAPTP301SPS19 mouse model of tau-dependent neurodegenerative disease accumulates p16INK4A-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation.

Also, the team was able to identify the specific type of cell that became senescent, says the senior author.

"Two different brain cell types called 'microglia' and 'astrocytes' were found to be senescent when we looked at brain tissue under the microscope," says the lead author. "These cells are important supporters of neuronal health and signaling, so it makes sense that senescence in either would negatively impact neuron health."

The finding was somewhat surprising, explains the senior author, because at the time their research started, a causal link between senescent cells and neurodegenerative disease had not been established.

"We had no idea whether senescent cells actively contributed to disease pathology in the brain, and to find that it's the astrocytes and microglia that are prone to senescence is somewhat of a surprise, as well," says the senior author.