New Research Demonstrates Second Direct Link Between Inflammasome Activation and Alzheimer's Disease

BOSTON and BONN, Germany, Nov. 20, 2019 /PRNewswire/ -- IFM Therapeutics, LLC (IFM), a privately-held biopharmaceutical company focused on developing therapies that modulate novel targets in the innate immune system to treat inflammatory disorders and cancer, today announced the publication of a new study in Nature that demonstrates NLRP3 inflammasome activation is required for tau pathology both directly and downstream of amyloid beta, in tauopathies (such as frontotemporal dementia) and Alzheimer's disease. The study findings further suggested that patients with these disorders could benefit from NLRP3 antagonists. The team publishing the pre-clinical research includes IFM clinical advisory board member, Michael Heneka, M.D., Director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at University Hospital of Bonn, IFM co-founder Eicke Latz, M.D., Ph.D., University of Bonn, and IFM Scientist James Stunden. The publication is available through Nature.

Tau Pathology, Alzheimer's Disease and Tauopathies

Tau protein is critical to maintaining healthy brain function, serving to stabilize neuron microtubules.  Contrary to normal neural activity, tau hyperphosphorylation and aggregation of tau proteins form the core of neurofibrillary tangles (NFTs), which are shown to be one of the pathological hallmarks of Alzheimer's disease (AD). Primary tauopathies, such as frontotemporal dementia (FTD), also present with neuroinflammation and cognitive deficits.

In the study, researchers analyzed both patients and animal models:

• To identify a potential role of the NLRP3 inflammasome in patients with tauopathy, the authors analyzed cortex samples from patients with FTD and found elevated ASC levels and increased active caspase-1 and mature IL-1β, indicative of NLRP3 inflammasome activation. 
• In a mouse model designed to mimic human tau FTD mutations, the mice developed tau pathology over time, and the presence of NLRP3 activation was also detected. It was also found that tau activated the NLRP3 inflammasome in an NLRP3-dependent manner.

"Our results indicate that the inflammasome and the inflammatory reactions it triggers play an important role in the emergence of tau pathology," said Michael Heneka, M.D. "This study provides a strong rationale for influencing tau pathology via the inhibition of the NLRP3 inflammasome. If tau pathology could be contained, this would be an important step towards a better therapy for those living with tauopathies and Alzheimer's disease."

The Inflammasome: Linking Amyloid Beta and Tau

Amyloid beta (Ab) is a protein that accumulates in the brain between the neurons, disrupting communication between brain cells and eventually killing them, making it the primary cause of AD. Aggregation of tau proteins, which accumulates within neurons, occurs later. Previous research conducted by Heneka and his team demonstrated when Aβ is deposited, it causes a pathological innate immune response, and activation of the NLRP3 inflammasome has been documented in the brains of patients with AD. In this current study, NLRP3 inflammasome is considered to be the missing link in the chain of events that lead to cell death, as it bridges the development from Ab pathology to tau pathology. "In showing that the NLRP3 Inflammasome directly leads to the decline associated with tau pathology in serious neurodegenerative diseases, this study underscores the potential of targeting this pathway," said H. Martin Seidel, Executive Vice President of Research and Development at IFM. "Having developed a first-in-class NLRP3 antagonist program within IFM Tre from a standing start into human trials, a program that was recently acquired by Novartis, we are particularly encouraged about the potential impact for patients with Alzheimer's disease and other tauopathies. The results further validate our team's drug development approach focused on novel targets of the innate immune system. We look forward to continuing to watch the research coming out of Dr. Heneka and Latz's labs, while we focus on the further progression of IFM's internal programs, including the efforts within IFM Due targeting the cGAS-STING pathway and our other exciting new targets."

About IFM Therapeutics, LLC

IFM Therapeutics (IFM) is a privately-held biopharmaceutical company based in Boston, Massachusetts. The Company was founded by an international group of preeminent scientists and physicians following the sale of IFM Therapeutics, Inc. (originally founded by Gary D. Glick and Atlas Venture) to Bristol-Myers Squibb. IFM's team has discovered and developed small molecules that modulate novel targets in the innate immune system as next-generation therapies for cancer, auto-immunity, and inflammatory disorders. IFM places each program (or set of related programs) in its own dedicated, independently financed, R&D-focused subsidiary company, which is supported by the common infrastructure, management team and resources of the IFM enterprise. For more information on IFM and its model, please visit https://www.ifmthera.com.

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