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Pictured: Flames attacking a brain/Nicole Bean for BioSpace Alois Alzheimer recognized more than a century ago the role of neuroinflammation in the development of the disease that would bear his name. “If you actually go back to his original drawings, he was drawing the cells, which today we know are microglia,” immune cells of the brain, said Bruce Lamb, executive director of the Paul and Carole Stark Neurosciences Research Institute at Indiana University School of Medicine and co-founder of Monument Biosciences, which is exploring neuroinflammation-targeted Alzheimer’s treatments. “So, he recognized way back, 120 years ago, that these cells were there” and that they could be playing a role in the disease process. Several studies have established a link between neuroinflammation and Alzheimer’s disease, and the culprit indeed appears to be microglia. “I think it’s very clear that, at least the minute amyloid is deposited in the brain and maybe even before, there’s a microglial response,” Lamb told BioSpace. And it’s this immune response that could be causing problems with neuronal function. Lamb said that over the last decade and a half, there has been a renewed interest in the role of microglia in Alzheimer’s, spurred in part by discoveries in the genetics of late-onset Alzheimer’s disease. Genome-wide association studies and the identification of rare mutations that occur in families have led to a list of Alzheimer’s-associated genes, and most of these are expressed in microglia, Lamb said. Meanwhile, transcriptomics, proteomics and metabolomics data from human cases and controls have revealed similar findings, he added. “A lot of the networks and pathways that are disturbed, especially in late-onset Alzheimer’s disease, are in these inflammatory networks.” Targeting TREM2 and More Working under the hypothesis that neuroinflammation contributes to the Alzheimer’s disease process, biotech companies are exploring different targets. Vigil Neuroscience is developing a candidate based on the role of TREM2-mediated microglial dysregulation in the disease process. Also targeting TREM2 is Alector Therapeutics, which describes its strategy as immuno-neurology. TREM2 is expressed on microglia in the brain, but it is really only expressed in response to amyloid deposits, Lamb explained. There is a signaling cascade downstream of TREM2 within the microglia, “and a lot of the other genes that are implicated in Alzheimer’s disease are also in microglia downstream of TREM2,” he said. At his own company, Lamb added, the team is initially targeting the PLCG2 and INPP5D genes, both of which are downstream of TREM2 and also have genetic associations with Alzheimer’s disease. Boston–based Cerevance is targeting a different gene, KCNK13, which is specific to and upregulated in the microglia. While others are also going after the NOD-like receptor protein 3 (NLRP3) inflammasome, Cerevance is looking to regulate inflammation only in the central nervous system, leaving peripheral immune cells ready and able to fight opportunistic infections, said CEO Craig Thompson. This is particularly important in Alzheimer’s, he added, because the patients tend to be older and frail. “Our thought was, is there a way to damped down the inflammation on the inflammasome but still [leave] other aspects of the NLRP3 that are helpful for normal immune system functioning?” In preclinical models, the company’s KCNK13-targeting asset, CVN293, had minimal impact on the peripheral immune system while reducing neuroinflammation in the brain, Thompson explained. Cerevance has shown that “we can tamp down the inflammation response, or the inflammasome, but keep all the other surveillance and other aspects of microglia still functioning as they should.” The company is now conducting a Phase I study of CVN293, with topline data expected in the second quarter of 2024. In Ohio, biotech NeuroTherapia was co-founded by anesthesiologist Mohamed Naguib, who found that microglia upregulated the cannabinoid type 2 (CB2) receptor, CEO Tony Giordano relayed in an interview with BioSpace. Naguib further found that “CB2 agonists were able to shift the microglia . . . from a proinflammatory phenotype to an anti-inflammatory phenotype,” which improved amyloid clearance and neuronal function in preclinical models, Giordano said. NeuroTherapia is developing a CB2 receptor agonist for Alzheimer’s disease called NTRX-07, which Giordano expects to enter Phase II trials in the third quarter of this year. “We believe that it’s the continued activation of the microglia and the production of the proinflammatory cytokines that starts to interfere with synaptic transmission and neuronal function,” Giordano explained. “Fortunately, it appears that if you can stop that activity, you’re going to get improvement in neuronal function.” A Multipronged Attack Ultimately, Giordano and Thompson agreed that treating Alzheimer’s disease will require a multifaceted attack. “Alzheimer’s is a very, very complex disease, and you’re not going to treat it with a single agent,” Giordano said. “It’s likely that you’re going to put together a cocktail and we really believe that neuroinflammatory inhibitors are going to be a part of that cocktail.” Thompson called Alzheimer’s “more of a constellation of diseases” and said that tackling it from multiple approaches will be “really important.” He teased that Cerevance is also looking at other approaches with some of its earlier compounds. While he wouldn’t reveal the targets, he said that, like KCNK13, “they’re very novel approaches.” Lamb added that anti-amyloid antibodies, including Eisai and Biogen’s Leqembi, appear to be working primarily through the microglia. “The microglia have these FC receptors which bind to the antibodies and then can actually remove amyloid from the brain,” he said. Amyloid-related imaging abnormalities (ARIA) has been the primary smudge on the surface of drugs like Leqembi and Eli Lilly’s donanemab. Lamb explained that this side effect is thought to be an inflammatory process. “We think it’s amyloid binding to blood vessels where there’s amyloid and that that is actually recruiting immune cells and leading to where there’s an immune dysfunction.” Accordingly, he said, there is a lot of interest in combination therapies with monoclonal antibodies and drugs targeting microglia “to either improve the removal of amyloid, or even better, prevent some of these side effects that are seen with these antibodies.” When asked which approach is most likely to lead to the next Alzheimer’s breakthrough, Lamb acknowledged he is biased, but said, “I certainly think the immune pathways . . . are near the front of that sort of discussion.” Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

Investigators revealed how genetic changes in certain types of brain cells may contribute to the inflammatory response seen in Alzheimer's disease. Study by Brigham investigators revealed how genetic changes in certain types of brain cells may contribute to the inflammatory response seen in Alzheimer's disease Immune-regulating brain cells known as microglia are known to play a role in the progression of Alzheimer's disease (AD). A new study by investigators from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, explores how the genetics of microglia contribute to neuroinflammation and, in turn, AD. The team revealed that a reduction of INPP5D, a gene found in microglia, results in neuroinflammation and increases the risk for AD. Their results, which have important implications for the design of microglia-centered therapeutics for Alzheimer's disease and related disorders, are published in Nature Communications. "We know that microglia play important roles in the healthy and diseased brain, but, in many cases the molecular mechanisms underlying this relationship are poorly understood," said corresponding author Tracy Young-Pearse, PhD, from the Department of Neurology at Brigham and Women's Hospital. "If we're able to identify and understand the significance of specific genes that play a role in neuroinflammation, we can more readily develop effective, targeted therapeutics." Neuroinflammation is important to monitor in people with neurodegenerative diseases, but it can be difficult to detect, especially in the early stages of AD. The earlier neurologists can identify it, the earlier they can treat it. Microglia are clearly involved in the process of neuroinflammation, but there are many unanswered questions regarding the molecular pathways involved. The team used a variety of experimental approaches to probe the relationship between levels of INPP5D and a specific type of brain inflammation, activation of the inflammasome. As part of their study, the team compared human brain tissue from patients with AD and a control group. They found lower levels of INPP5D in the tissues of patients with AD and when INPP5D was reduced, it activated inflammation. In parallel, they used living human brain cells derived from stem cells to study the intricate molecular interactions within microglia that mediate inflammatory processes with a reduction of INPP5D. These studies identified specific proteins that could be inhibited to block inflammasome activation in microglia. Although the team's work represents the most comprehensive analysis of INPP5D in the AD brain, it remains to be determined whether INPP5D should be targeted with therapeutics. The team notes that their findings suggest INPP5D activity in AD brains is complex and future studies are needed to understand if INPP5D can be targeted to prevent cognitive decline in patients with AD. "Our results highlight an exciting promise for INPP5D, but some questions still remain," said Young-Pearse. "Future studies examining the interaction between INPP5D activity and inflammasome regulation are essential to improve our understanding of microglia in AD and to help develop a comprehensive toolbox of therapeutics that can be deployed to treat each of the molecular roads that lead to AD."

Researchers are studying how the reduction of a gene variant found in the brain's immune cells could diminish the risk of late-onset Alzheimer's disease. Indiana University School of Medicine researchers are studying how the reduction of a gene variant found in the brain's immune cells could diminish the risk of late-onset Alzheimer's disease. The research team, led by Adrian Oblak, PhD, assistant professor of radiology and imaging sciences, and Peter Bor-Chian Lin, a PhD candidate in the Medical Neuroscience Graduate Program at Stark Neurosciences Research Institute, recently published their findings in Alzheimer's & Dementia: The Journal of the Alzheimer's Association. They focused their investigation on INPP5D, a microglia-specific gene that has been shown to increase the risk for developing late-onset Alzheimer's disease. Microglia are the brain's immune cells and there are multiple microglial genes associated with neurodegeneration. Oblak said the team's previous data revealed that elevated levels of INPP5D in Alzheimer's disease lab models resulted in increased plaque deposition. Knowing this, they aimed to understand how reducing expression of INPP5D might regulate disease pathogenesis. Using models in the lab, the researchers reduced the expression of the gene by at least 50 percent -- called haplodeficiency -- rather than completely knocking out the expression of the gene to mimic the treatment of pharmacological inhibitors targeting INPP5D as therapeutic strategies. "INPP5D deficiency increases amyloid uptake and plaque engagement in microglia," Oblak said. "Furthermore, inhibiting the gene regulates microglial functions and mitigates amyloid pathology that are likely mediated by TREM2-SYK signaling pathway activation." The gene deficiency also led to the preservation of cognitive function in the lab models. By reducing the expression of the gene in the brain, it created a less neurotoxic environment and improved the movement of microglia -- which act as the first line of defense against viruses, toxic materials and damaged neurons -- to clear amyloid deposits and plaques. "These findings suggest that mitigating the function of INPP5D can result in a protective response by diminishing disease risk and mitigating the effect of amyloid beta induced pathogenesis," Lin said. The research team is actively working with the IU School of Medicine-Purdue University TaRget Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Drug Discovery Center to develop therapies to reduce INPP5D function in Alzheimer's disease.