New Research Demonstrates Direct Link between Inflammasome Activation and Amyloid-β Pathology in Alzheimer's Disease

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BOSTON and BONN, Germany, Dec. 20, 2017 /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 demonstrating that the activation of inflammasomes in the innate immune system is connected to seeding and spreading of amyloid-β (Aβ) in Alzheimer's disease, as well as demonstrating the potential of this pathway for new therapeutic targets in the treatment of the disease. The team publishing the pre-clinical research includes IFM co-founder Eicke Latz, M.D., Ph.D., University of Bonn, and newly appointed IFM clinical advisory board member, Michael Heneka, M.D., Director of the Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital of Bonn, Germany. The publication is available through Nature.

In Alzheimer's disease (AD), a classic hallmark of the neurodegenerative disorder is the assembly of Aβ peptides into pathological oligomers accompanied by the subsequent aggregation into plaques in the brain that lead to cell damage and memory loss. This study demonstrates key insights into the pathology and potential new therapeutic targets for future research.

"For the first time, research has demonstrated a hardwiring of innate immune activation and Aβ aggregation and seeding in Alzheimer's disease, a highly-complex, relentless and progressive disease affecting millions of people," said Michael Heneka, M.D., KBFZ, University Hospital of Bonn. "These data provide insight into the etiology of the disease through activation of NLRP3 inflammasomes that contribute to the seeding and spreading of the disease, while demonstrating the use of anti-ASC antibodies to block the amyloid-β pathology."

Role of inflammasome activation in seeding and spreading of AD

Previous research has demonstrated that 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. The NLRP3 inflammasome activation has also been shown to result in the formation of specks of the inflammasome adapter protein ASC (apoptosis-associated speck-like protein containing a CARD) in the microglia.

In this pre-clinical study, ASC specks were shown to bind to Aβ and increase oligomerization and aggregate formation, suggesting inflammasome-driven cross-seeding can favor Aβ plaque development and disease pathology.

Reduction of Aβ deposition through ASC-speck antibody

In order to better understand how this novel pathway contributes to disease pathogenesis, an anti-ASC speck antibody was co-applied in both cultured cells and mouse models. Indeed, anti-ASC prevented ASC driven Aβ oligomerization and aggregate formation in a concentration dependent manner. Further experiments showed that mice receiving injections of ASC co-incubated with specific anti-ASC antibody had a reduced amounts of Aβ oligomers. Together, this research shows that inhibiting ASC from binding to Aβ can reduce its aggregation, highlighting the role this inflammatory pathway may play in future of therapeutic development.

"At IFM Therapeutics, our team is focused on improving the lives of patients with inflammatory disorders by developing transformative medicines that precisely target the innate immune system," said Martin Seidel, Ph.D., EVP of Research and Development, IFM Therapeutics. "Identifying clinically validated targets in this disease area has been a major challenge for the scientific community, but we are encouraged that the research published in Nature provides scientific evidence of the role of the innate immune system in the pathology of the classic hallmarks of Alzheimer's disease. As our team focuses on inhibitors of NLRP3, this research highlights the potential to modulate the inflammatory pathways associated with Alzheimer's disease with the goal of developing new treatment options for patients."

About IFM Therapeutics, LLC

IFM Therapeutics, LLC is a privately held biopharmaceutical company based in Boston, Massachusetts. The company was founded by an international group of preeminent scientists and physicians who have spent decades understanding innate immunity and the role it plays in regulating the immune system. IFM's team has discovered and developed small molecules that modulate novel targets in the innate immune system as next-generation therapies for cancer, autoimmunity, and inflammatory disorders. For more information, please visit www.ifmthera.com.    

SOURCE IFM Therapeutics

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