Principal Investigator
The Ising lab focuses on the role of cell death and senescence of microglia, the innate immune cells of the brain, in the development and progression of aging-associated tauopathies such as Alzheimer’s disease.
Alzheimer’s disease is the most common form of dementia and as a tauopathy, it is characterized by intraneuronal accumulation of the tau protein. Another important hallmark of tauopathies is chronic neuroinflammation. Hence, microglia play an important, but incompletely understood role in these diseases. Upon treatment with specific stimuli, including but not limited to tau, microglia can activate a defense mechanism called the NLRP3 inflammasome. This can ultimately lead to the execution of pyroptosis, a lytic, programmed cell death creating a pro-inflammatory environment and releasing factors that potentially affect other cells including neurons in the brain.
In her postdoc time, Dr. Ising has already shown that NLRP3 inflammasome-dependent release of the pro-inflammatory factor IL-1β from microglia leads to an activation of tau kinases and inhibition of one of the major tau phosphatases via downstream signaling initiated in neurons. In addition, she showed that the tau protein itself can induce NLRP3 inflammasome activation in microglia (Ising et al., Nature 2019). Present work of the Ising lab focuses on mechanisms in pyroptosis execution and other factors released in this process as well as on potential new players in the NLRP3 inflammasome pathway.
However, microglia are also able to go into senescence, a well-known hallmark of aging. Senescence is a cellular state characterized by irreversible cell cycle arrest, metabolic dysfunction and secretion of a senescence-associated secretory profile (SASP), that can also modulate the microenvironment in the brain and affect neighboring cells. The Ising lab showed that the tau protein is also able to induce microglial senescence (Karabag et al., J Neurochem 2023). Since the composition of the SASP and other senescence features greatly depend on cell type and senescence inducer, they now continue to study underlying mechanisms, related SASP factors and their effect on neurons and other bystander cells.
Tauopathies are detrimental neurodegenerative diseases. The Ising lab aims to identify potential new treatment targets by unraveling underlying disease mechanisms related to neuroinflammation.
The overarching goal of Dr. Ising and her team is to find new therapeutic strategies for tauopathy patients. To this end, they study underlying molecular mechanisms in Alzheimer’s disease and other tauopathies as a fundamental understanding is crucial for further developments. Here, they focus on the neuroinflammatory component of these diseases as this clearly influences disease progression. The NLRP3 inflammasome is of general interest to the group as it has been involved not only in pyroptotic cell death, but also in cellular senescence. The current state of research suggests that both, microglial pyroptosis and senescence, might be detrimental in tauopathies, rendering overlapping pathways attractive for treatments.
The scientists led by Dr. Ising now aim to identify commonalities and differences in microglia cell death and senescence and to understand their relation to brain aging and tauopathies. To this end, they aim to:
Ultimately, the team will then test if any of the factors/proteins identified could serve as a potential new treatment target.
Principal Investigator