Neuroinflammation: The Natural Next Alzheimer’s Target?

Brain on Fire_Nicole Bean for BioSpace

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.

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