Can getting rid of senescent cells in the brain reduce memory loss?

By: Alejandro Lopez-Ramirez, Lab Manager in the Ellerby lab and Lauren Wimer, Dominican University of California graduate student in the Kapahi lab.

Tau tangles, aggregates of tau proteins that clump together in the brain, are implicated in many brain pathologies including neuron loss and memory loss.  Another process associated with neuron loss is cellular senescence.  Senescent cells –  cells that no longer have the ability to grow and divide – secrete specific biomarkers which distinguish them from normal cells.  These markers are observed in a variety of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, although it is still unknown why senescent cells are closely associated with the onset of these diseases, or how tau tangles contribute to certain neurodegenerative conditions.

 A team from the Mayo Clinic investigated by asking if there is significant cognitive improvement and a decrease of tau tangles if senescent glial cells – the “support cells” in the brain that help make sure the neurons can do their job – are cleared. Their approach was to build a mouse model that contained two specific genes that would actively remove senescent cells. In addition to the genetic correction for senescent cells, the mouse itself is prone to express high levels of tau tangles in neurons. As the team proceeded with the removal of senescent cells, the induced tau tangle mice began to improve. Cognitive functions were restored according to various tests they performed on the mice. Molecular experiments confirmed that markers of senescent cells decreased and markers of both neurons and glial cells increased.

The work performed by the Mayo team complements the groundbreaking work  being done at the Buck Institute by Dr. Julie K. Andersen. Dr. Andersen and her lab currently work with a mouse model of Parkinson’s disease (PD) to reverse pathologies by clearing inflammatory cells. It is believed that by clearing these senescent astrocytes they are able to prevent symptoms of PD from occurring in a live mammal across several stages of age. “Chronic inflammation fueled by senescence drives many age-related diseases, and it’s quite possible that Parkinson’s is among them,” says Dr. Andersen. The work being performed by Dr. Andersen and her lab is vital in understanding the effects of senescent cell clearing on specific neurodegenerative diseases and identifying possible novel treatments.

 Future directions with this current research could lead us to ask how well we can control the number of senescent cells being cleared. For example, are we able to construct a dosage dependent treatment so that we can improve cognitive and neuronal plasticity without disturbing natural necessary senescence? Can we make the treatment localized in one area instead of it affecting the entire body?

This research is affecting the field in a very positive way because the Mayo team has found a way to relieve tau tangles in neurons. In addition to the attenuation of neurological deficiencies, the lab has also further applied more information of where senescent cells can cause further harm aside from just being seen as silent cells. 

Letter | Published: 19 September 2018

Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline

Tyler J. Bussian, Asef Aziz, Charlton F. Meyer, Barbara L. Swenson, Jan M. van Deursen & Darren J. Baker 

Nature volume 562, pages 578–582 (2018)