A recent study regarding the application of immunotherapy for Alzheimer’s disease has surfaced in the journal Science Translational Medicine.
In this investigation, scholars from Washington University in St. Louis delineate a method employing antibodies to reinstate the immune cells of the nervous system's capacity to eliminate unwanted debris, which could instigate Alzheimer’s disease.
“At present, there exists no remedy for Alzheimer’s disease, and the existing treatments merely provide partial relief from symptoms,” stated Marco Colonna, MD, the Robert Rock Belliveau professor of pathology and immunology at Washington University in St. Louis and the corresponding author of this research, in conversation with Medical News Today.
“Specific monoclonal antibodies, such as lecanemab and aducanumab, have secured FDA [Food and Drug Administration] endorsement for Alzheimer’s therapy. Other monoclonal antibodies heighten microglial responses to amyloid-beta pathology by triggering the TREM2 receptor and are currently undergoing clinical trials,” he informed us.
“Nevertheless, the efficacy of these therapies necessitates further examination,” Colonna appended. “Thus, it is imperative to explore additional approaches that may potentially offer superior effectiveness or complement existing monoclonal antibody treatments to bolster overall efficacy.”
How immune cells in the brain may help fight dementia
In this investigation, scientists employed a rodent model to evaluate their approach, concentrating on directing proteins that govern the function of microglia — a subset of immune cells — within the nervous system.
"Microglia react to cues from the tissue surroundings, which can either trigger or suppress their activity," elucidated Colonna. "Their principal function involves eliminating harmful substances accumulating in the brain through phagocytosis [a process where cells 'ingest' foreign matter]. These toxins emit signals that stimulate microglia to engulf them."
"At the same time, microglia are tasked with protecting the brain's vital elements, which emit signals to discourage microglial activation," he added. "To augment microglial phagocytic capabilities, we can either administer activating signals or hinder inhibitory ones. Our approach centers on suppressing receptors that hinder microglial phagocytosis."
Previous research has indicated that microglia could potentially mitigate neuroinflammation and eliminate the toxic buildup of proteins such as tau and beta-amyloid, linked to Alzheimer's disease.
An antibody that may help clear toxic plaques in the brain
Colonna and his colleagues additionally examined the influence of the LILRB4 receptor, situated on the microglia within the brain, and its potential role in the progression of Alzheimer’s disease.
"LILRB4, a receptor present on microglia in the brain, interacts with ApoE, a lipid-carrying protein abundant in the brain and a component of amyloid plaques linked to Alzheimer’s disease," Colonna detailed. "Certain variations of the ApoE gene in humans elevate the susceptibility to Alzheimer’s."
Initially, scientists detected elevated levels of LILRB4 on the surfaces of microglia in brain tissue specimens obtained from individuals afflicted with Alzheimer’s disease.
Subsequently, researchers utilized a mouse model engineered to produce the human LILRB4 receptor. Their trials demonstrated that the LILRB4 receptor impeded the capacity of microglia to engage with beta-amyloid plaques.
Administering antibodies targeting LILRB4 to the mice led to reduced levels of beta-amyloid in the brain, heightened microglial function, and reversed certain behavioral alterations observed during maze assessments associated with beta-amyloid buildup, as identified by the researchers.
"We found that when ApoE attaches to LILRB4, it hampers the microglia's capacity to eliminate amyloid plaques," Colonna elaborated.
“On the other hand, using a specific antibody to block ApoE from binding to LILRB4 actually boosts microglia’s ability to clear away these plaques. This suggests that treating Alzheimer’s patients with this antibody could potentially help in removing amyloid plaques.”
– Marco Colonna, MD
"Considering our discoveries, we believe that administering this particular monoclonal antibody to individuals with Alzheimer’s could potentially assist in the brain's clearance of amyloid plaques and other detrimental proteins that accumulate in neurodegenerative disorders," he elaborated. "Moreover, this therapy might also be integrated with other experimental treatments to enhance their effectiveness."
Neuroimmunology: A new approach to Alzheimer’s treatment
After assessing this study, Karen D. Sullivan, PhD, a certified neuropsychologist, founder of I CARE FOR YOUR BRAIN, and a Reid Healthcare Transformation fellow at FirstHealth of the Carolinas in Pinehurst, NC, who was not involved in the research, informed MNT that it offers additional evidence of the potential of neuroimmunology to address and, ideally, eventually cure Alzheimer’s disease.
"These research findings lend further support to the notion that monoclonal antibodies can impede the accumulation of beta-amyloid, recognized as one of the primary indicators of the condition," Sullivan remarked.
"What remains unclear is the impact of reducing amyloid through this novel mechanism, the anti-LILRB4 microglia signaling, on cognitive function and the progression of the disease," she pointed out.
"With the imminent 'aging of the global population,' we are on the brink of facing a surge in the number of individuals living with dementia," Sullivan emphasized. "The economic and emotional burden of this substantial rise in diagnoses of the neurodegenerative condition is immense, and we require all available resources directed towards the provision of care and medical supervision for these illnesses."
Working toward more effective Alzheimer’s treatments
MNT also conversed with Manisha Parulekar, MD, who serves as the Director of the Division of Geriatrics at HackensackUMC, co-director of the Center for Memory Loss and Brain Health, and associate professor at the Hackensack Meridian School of Medicine in New Jersey, regarding this study.
Similar to Sullivan, Parulekar was not engaged in this research.
"Microglia play crucial roles in various brain protective functions such as upholding the blood-brain barrier, which shields the brain from detrimental substances like toxins," Parulekar elucidated.
"This research is delineating the potential consequences of impairing these defensive functions in the causation of Alzheimer’s disease, as well as potential interventions. We are continuing our efforts towards discovering effective therapies for Alzheimer’s. The restoration of microglial function could represent a viable treatment avenue," she conveyed.
"Alzheimer’s disease stands as the predominant type of dementia, impacting millions globally," Parulekar emphasized. "The incidence is anticipated to surge substantially in forthcoming decades owing to aging demographics. It represents a global public health emergency, imposing considerable financial and caregiving burdens on families, communities, and societies."
The specialist underscored the absence of an efficacious treatment capable of halting or reversing disease advancement.
"Our ongoing investigations indicate that Alzheimer’s disease likely arises from multiple mechanisms or risk factors," she elaborated. "Hence, it is imperative to explore diverse therapeutic avenues capable of halting or decelerating the neurodegenerative process."
