Probing the Innate Immune System’s Role in Alzheimer’s Disease

A Cleveland Clinic research team is taking an innovative tack to combat Alzheimer’s disease (AD) by focusing a multitude of investigations on the contributions of the innate immune system and chronic inflammation.

Although amyloid deposits and neurofibrillary tangles containing tau protein are well-established hallmarks of brain pathology in AD, attempts to modify disease development and progression with drugs directed at these targets have so far failed. In recent years, inflammation has come to be recognized as an important feature in patients with AD, but its role has not been well characterized.

“Evidence suggests that neuroinflammation may not just be a response to amyloid plaques and neurofibrillary tangles but may actually contribute directly and significantly to the pathogenesis of Alzheimer’s disease,” says Tara DeSilva, PhD, a research scientist with the Department of Neurosciences in Cleveland Clinic’s Lerner Research Institute and a leader of Cleveland Clinic’s investigations in this realm. “This opens up potential new targets for developing novel therapies.”

Interdisciplinary focus on APOE4 and TREM2 genetic variants

The research — funded by a Cleveland Clinic Research Centers of Excellence grant to Dr. DeSilva and James Leverenz, MD, Director of Cleveland Clinic’s Lou Ruvo Center for Brain Health, Cleveland — is taking a decidedly interdisciplinary approach. Lerner Research Institute staff Lynn Bekris, PhD, also of the Genomic Medicine Institute, and Shaun Stauffer, PhD, Director of the Cleveland Clinic Center for Therapeutics Discovery, will also be key investigators.

By drawing on studies and expertise across clinical neurology, brain imaging, neuroimmunology, genetics, proteomics, rodent behavior, biomarker development and drug discovery, the investigators aim to delve widely and deeply into the underexplored relationship between inflammation and AD.

Using mouse models of AD and ongoing human-based imaging, genetic and biomarker studies of AD and normal aging, the researchers are focusing on high-risk genetic factors for AD: APOE4 (a variant of apolipoprotein E) and rare variants of TREM2 (triggering receptor expressed on myeloid cells 2). Evidence suggests that these factors aberrantly modulate microglial function to alter phagocytosis and expression of inflammatory cascades.

Key initial questions

The research is initially aimed at answering four basic questions:

• Does inflammation enhance amyloid plaque formation?
• Does amyloid plaque formation alter inflammatory markers?
• Do genetic risk factors influence the relationship between inflammation and the brain changes of AD?
• Does pharmacologically targeting inflammation alter neurodegeneration and cognitive decline?

Specific studies include brain imaging to characterize plaque and white matter alterations, blood plasma analysis to assess immune cell activation and discover inflammatory markers for deep phenotyping, and analysis of postmortem brains to search for clues of innate immune responses by studying microglial activation and phagocytosis in gray and white matter.

“Developing an infrastructure for comprehensive assessment of Alzheimer’s disease is expected to provide highly relevant insights into the role of the immune system,” Dr. DeSilva explains. “The interplay of mouse model and human studies will drive basic science and set the stage for drug discovery.”

A bench-to-bedside emphasis

Research collaboration in the neurosciences and investigations with a high likelihood of transitioning to clinical trials are prime considerations in the granting of the Lerner Research Institute’s Research Centers of Excellence awards, which are intended to spur innovative team science and accelerate discoveries to improve patient care. Previous awardees have gone on to secure large competitive federal and foundation grants.

Other awardees this year include investigations focusing on epilepsy and its comorbidities and on therapeutic development for brain tumors.

An important goal of the current AD research is to develop small molecules to target immune responses for preclinical trials in animal models of the disease. “New therapeutic targets are desperately needed for Alzheimer’s disease,” says co-investigator Dr. Leverenz.

He notes that of the five currently approved drugs to treat AD symptoms, none slows or halts disease progression. “Investigations of anti-amyloid therapeutic agents have thus far been disappointing and alternative approaches need to be explored for this devastating disease,” he adds.

The Cleveland Clinic research team has already identified molecular targets to modulate microglia-mediated innate immune responses aimed at stopping or slowing the progression of AD pathology. They will conduct target validation of small molecules in human immortalized microglial cells, followed by in vivo testing in mice.

“We have high expectations that targeting signature forms of brain inflammation as a fundamental early event in AD pathology will prove to be a more fruitful strategy to halt or even prevent disease progression,” says Dr. Stauffer. “This research grant is allowing us to lay an important foundation for a whole new avenue of research and drug development.”