Direct link to 'inflammasome activation' for AD?

BOSTON & BONN, Germany—Toward the end of December, IFM Therapeutics LLC, a privately held biopharmaceutical company focused on developing therapies that modulate novel targets in the innate immune system to treat inflammatory disorders and cancer, announced results of research that reportedly demonstrates that the activation of inflammasomes in the innate immune system is connected to seeding and spreading of amyloid-β (Aβ) in Alzheimer’s disease.

The results of this preclinical work were published in the journal Nature and, according to IFM, the research also points to the potential of this pathway for new therapeutic targets in the treatment of the disease.

The research team includes IFM co-founder Dr. Eicke Latz, of the University of Bonn in Germany, and also newly appointed IFM clinical advisory board member Dr. Michael Heneka, who is director of the Department of Neurodegenerative Diseases and Gerontopsychiatry at the University Hospital of Bonn.

In Alzheimer’s disease (AD), one of the hallmarks of the neurodegenerative disorder is the assembly of Aβ peptides into pathological oligomers, which then leads to the build-up of plaques in the brain that lead to cell damage and memory loss.

“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 Heneka. “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.”

According to the researchers, 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 fact, Heneka has been an instrumental part of some of that earlier research, including “NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice,” published in January 2013 in Nature, and “Innate immunity in Alzheimer's disease,” published in January 2015 in Nature Immunology.

And looking at an additional study by other researchers, the abstract for the study “The NLRP3 inflammasome in Alzheimer's disease,” published in Molecular Neurobiology in December 2013, noted: "Innate immunity and inflammatory response plays an important role in the pathogenesis of Alzheimer's disease (AD). As the major resident immune cells in the brain, microglia cells constantly survey the microenvironment and are activated by and recruited to senile plaques. Subsequently, they can phagocytose amyloid-β (Aβ) and secrete pro-inflammatory cytokines that influence the surrounding brain tissue. Recently, a wealth of information linking the microglia-specific activation of NLRP3 inflammasome to AD pathogenesis has emerged.”

In that study, the team reviewed the activation mechanisms of the NLRP3 inflammasome in microglia and several downstream effects in the brain, “demonstrating that toxic Aβ peptide can light a fire in NLRP3 inflammasome and eventually induce AD pathology and tissue damage. More importantly, it has been demonstrated that inhibition of NLRP3 could largely protect from memory loss and decrease Aβ deposition in AD transgenic mouse model.”

In this more recent preclinical study involving IFM, published Dec. 21 by Nature and titled “Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease,” 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.

The team co-applied an anti-ASC speck antibody in cultured cells and in mouse models to better understand how this novel pathway contributes to disease pathogenesis, and the research indicated that anti-ASC prevented ASC-driven Aβ oligomerization and aggregate formation in a concentration-dependent manner.

Additional experiments showed that mice receiving injections of ASC co-incubated with a specific anti-ASC antibody demonstrated reduced amounts of Aβ oligomers.

“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 Dr. Martin Seidel, IFM’s executive vice president of research and development. “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.”