Dr. Christina Ising

Dr. Christina Ising CECAD

Dr. Christina Ising

Principal Investigator, Research Group Leader

+49 221 478 84166


SFB 1403

CECAD Forschungszentrum
Joseph-Stelzmann-Str. 26

50931 Köln

Connecting cell death, senescence and neuroinflammation in Alzheimer’s disease and other tauopathies

Among others, Alzheimer’s disease (AD) and certain types of Frontotemporal dementia belong to a group of neurodegenerative diseases collectively termed tauopathies as they are characterized by intracellular accumulation of the tau protein in neurons. Ultimately, this leads to neuronal death and deterioration in cognitive function. AD is the most common form of dementia worldwide and as aging is the main risk factor to develop AD, numbers are expected to rise in our aging society. To date, no effective disease-modifying treatment for AD or other tauopathies is available. Over the past years, it has become increasingly evident that chronic neuroinflammation plays an important role in AD and other tauopathies, but the underlying mechanisms and the potential for inflammation-based treatment strategies remain elusive.

Our research: The Ising lab focuses on the role of microglia, the innate immune cells of the brain, in the development and progression of tauopathies. Upon activation, microglia can die by pyroptosis, a lytic, programmed cell death creating a pro-inflammatory environment and releasing factors that potentially affect other cells in the brain. However, microglia are also able to go into senescence, a cellular state characterized by irreversible cell cycle arrest, metabolic dysfunction and secretion of a senescence-associated secretory profile (SASP) that can affect neighboring cells. To date, it remains unclear when a cell goes into senescence or cell death and how exactly these pathways affects bystander cells and intraneuronal tau pathologies. Therefore, we investigate how microglia cell death and senescence contribute to tauopathies on multiple levels.

Our goals: The overarching goal of our research is to identify new potential treatment targets for tauopathy patients. To this end, we aim to characterize new molecular mechanisms in microglia cell death by investigating the function of cell death-related genes in tauopathies. Additionally, we aim to better define cellular senescence in microglia and other cells in the brain to investigate how cellular senescence affects tau pathologies on a molecular level.

Our successes: Dr. Ising previously worked on the role of the NLRP3 inflammasome in tauopathies. The NLRP3 inflammasome is an important defense mechanism in microglia and its activation leads to secretion of pro-inflammatory IL-1β and ultimately pyroptotic cell death. While working in Prof. Heneka’s lab, Dr. Ising showed that the NLRP3 inflammasome is activated in the brains of Frontotemporal dementia patients as well as in the brains of a tauopathy mouse model. Combining the tauopathy mouse model with mice harboring genetic deletions of important NLRP3 inflammasome components reduced levels of pathological, hyperphosphorylated and aggregated tau in the brain and ameliorated learning and memory deficits. Mechanistically, she found that IL-1β secreted by microglia binds to the IL-1 receptor on neurons, which leads to an activation of tau kinases and inhibition of one of the major tau phosphatases via downstream signaling initiated in the neurons. Interestingly, she also identified the tau protein as one of the activators of the NLRP3 inflammasome (Ising et al., Nature 2019). Therefore, modulation of the NLRP3 inflammasome pathway could provide a potential new treatment strategy for tauopathy patients.

In a second study in Prof. Heneka’s lab, Dr. Ising investigated the involvement of the immune checkpoint PD-1/PD-L1 in Alzheimer’s disease (AD). This checkpoint is an important inhibitory regulator of the immune system and is also involved in programmed death signaling. Dr. Ising and her colleagues found that in AD, but not control patients, the receptor PD-1 is expressed by microglia while astrocytes express the ligand PD-L1. PD-1 deletion from microglia resulted in an exacerbated inflammatory response and reduced phagocytosis of amyloid-beta. In line with this, loss of PD-1 in an AD mouse model increased formation of amyloid-beta plaques, one of the pathological hallmarks seen in the brains of AD patients (Kummer*, Ising* et al., EMBO J 2021). This shows that the PD-1/PD-L1 axis has an important role in regulating the immune response in AD and that boostering its function could be a new therapeutic approach that should be explored in detail.

Our methods/techniques: The Ising lab uses genetically-modified mice to model tauopathies in vivo and primary cell culture to investigate underlying molecular mechanisms in vitro. For our analyses, we use many standard molecular biology, immunohistological and biochemical techniques in combination with behavior tests as well as proteomic and metabolomic approaches.



CECAD Cooperations
EXTERNAL Cooperations
  • Prof. Dr. Michael Heneka, University of Luxembourg, Luxembourg
  • Prof. Dr. Luc Buée, University of Lille, Inserm, France