An experimental compound, meticulously developed through extensive research at Northwestern University, has showcased compelling evidence of its capacity to intervene in the earliest stages of Alzheimer’s disease, potentially averting the onset of memory impairment and cognitive decline. This groundbreaking work, detailed in a recent scientific publication, introduces a novel therapeutic strategy that targets the insidious molecular events preceding overt neurological damage.
At the heart of this discovery lies the identification of a previously unrecognized and particularly pernicious variant of amyloid beta oligomers. These toxic molecular assemblies, characterized as clusters of peptides, are now understood to be potent instigators of a cascade of detrimental changes within the brain. Their presence is strongly correlated with the initial stages of neuronal dysfunction, the activation of inflammatory processes, and the heightened reactivity of the brain’s immune cells, collectively contributing to the pathological landscape of Alzheimer’s.
The investigational drug, a precisely engineered small-molecule agent designated NU-9, has demonstrated a remarkable ability to diminish the concentration of this specifically toxic amyloid beta oligomer subtype. In a sophisticated animal model designed to mimic the progression of Alzheimer’s disease, NU-9 treatment resulted in a substantial reduction in the damage orchestrated by these aberrant protein clusters. The research team posits that by addressing these foundational pathological alterations at their very inception, NU-9 holds the significant promise of either preventing the debilitating cascade of neurotoxic events that ultimately leads to neuron destruction or substantially delaying their onset.
This breakthrough research illuminates a promising new avenue for therapeutic intervention, one that focuses on confronting Alzheimer’s disease in its nascent, pre-symptomatic phases. The implications are profound, suggesting a future where interventions can be deployed before the irreversible ravages of cognitive impairment and other debilitating symptoms manifest. The comprehensive findings of this study are slated for publication in the esteemed journal Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association on December 18th, marking a significant milestone in the scientific discourse surrounding neurodegenerative disorders.
According to Daniel Kranz, the lead author of the study and a recent Ph.D. graduate from Northwestern’s Interdisciplinary Biological Sciences (IBiS) program, the disease’s insidious nature begins decades before any clinical signs become apparent. He elaborated that crucial early events, such as the accumulation of toxic amyloid beta oligomers within neurons and the subsequent activation of glial cells, occur long before memory loss becomes a discernible symptom. Kranz emphasized that by the time observable symptoms emerge, the underlying pathological processes are already significantly advanced, a factor he believes has contributed to the failure of numerous previous clinical trials that initiated treatment at a later stage. His research team’s approach, administering NU-9 prior to the onset of symptoms, effectively models this critical, pre-symptomatic therapeutic window.
Kranz’s doctoral advisor and the study’s corresponding author, William Klein, a distinguished professor of neurobiology at Northwestern’s Weinberg College of Arts and Sciences and a co-founder of Acumen Pharmaceuticals, has dedicated his expertise to understanding Alzheimer’s disease. Acumen Pharmaceuticals is currently developing a therapeutic monoclonal antibody designed to target the very subtype of amyloid beta oligomers identified in this study, which is already undergoing clinical trials. The invention of NU-9 is attributed to Richard Silverman, a pivotal co-author of the study. Professor Silverman, renowned for his prior invention of pregabalin (Lyrica), a medication used to manage fibromyalgia, nerve pain, and epilepsy, holds the Patrick G. Ryan/Aon Professorship in Weinberg’s Department of Chemistry and is the founder of Akava Therapeutics, a startup company actively engaged in the commercialization of NU-9, now referred to as AKV9.
The genesis of NU-9 can be traced back approximately fifteen years, stemming from Professor Silverman’s extensive, multi-year endeavor to develop a small-molecule compound capable of preventing the aggregation of toxic proteins implicated in neurodegenerative diseases. By 2021, NU-9 had already demonstrated significant efficacy in animal models of amyotrophic lateral sclerosis (ALS), successfully clearing toxic SOD1 and TDP-43 proteins and restoring functionality to upper motor neurons. In a testament to its therapeutic potential, NU-9 received clearance from the U.S. Food and Drug Administration in 2024 to commence human clinical trials for ALS.
More recently, in an earlier phase of their research, Professor Silverman, alongside Professors Klein and Kranz, established that NU-9 possesses the capability to effectively address Alzheimer’s disease. In a prior study, NU-9 exhibited its ability to clear toxic amyloid beta oligomers from laboratory-grown brain cells derived from the hippocampus, a brain region critically involved in learning and memory processes. Professor Klein explained that in both ALS and Alzheimer’s disease, cells suffer from the detrimental accumulation of toxic proteins. He further noted that while cells possess an intrinsic mechanism for clearing these proteins, this pathway becomes compromised in neurodegenerative conditions like ALS and Alzheimer’s. NU-9, he elaborated, acts by restoring and supporting this vital cellular rescue pathway.
To further rigorously investigate the drug’s potential in combating Alzheimer’s disease, the research team focused on evaluating its efficacy in halting the earliest forms of cellular damage. In the newly published study, NU-9 was administered to a pre-symptomatic mouse model engineered to exhibit Alzheimer’s-like pathology. The mice were given a daily oral dose of the compound for a duration of sixty days.
The outcomes of this intervention were remarkably significant. NU-9 treatment led to a substantial reduction in reactive astrogliosis, an inflammatory response that typically escalates long before any overt symptoms of the disease become evident. Concurrently, the number of toxic amyloid beta oligomers that had bound to astrocytes—the star-shaped glial cells responsible for neuronal support and inflammation regulation—experienced a dramatic decrease. Furthermore, an abnormal manifestation of the protein TDP-43, a recognized hallmark of neurodegenerative diseases and a known contributor to cognitive impairments, was also sharply reduced in the treated mice.
Professor Klein described these results as "stunning," highlighting NU-9’s "outstanding effect on reactive astrogliosis, which is the essence of neuroinflammation and linked to the early stage of the disease." The observed improvements were not confined to specific brain regions but spanned multiple areas, indicating that NU-9 exerts a beneficial, brain-wide anti-inflammatory effect.
During their investigation into the effects of NU-9 on the pre-symptomatic mouse model, the research team unearthed an unexpected factor contributing to the disease’s progression. For many years, the scientific community has broadly considered amyloid beta oligomers to be more toxic than the larger amyloid beta fibrils that eventually form the characteristic plaques seen in later stages of Alzheimer’s disease. However, this new research reveals that not all amyloid beta oligomers are created equal. The Northwestern scientists have successfully identified a uniquely problematic subtype.
Kranz explained that they have identified a distinct amyloid beta oligomer subtype that appears intracellularly within neurons and on the surface of nearby reactive astrocytes very early in the disease process, potentially serving as a primary instigator of the initial Alzheimer’s pathology. This specific subtype, provisionally named ACU193+ due to its detection by the ACU193 antibody, was observed to emerge within stressed neurons. Subsequently, these oligomers appear to migrate and attach to the surfaces of adjacent astrocytes. It is hypothesized that when ACU193+ oligomers bind to astrocytes, they may trigger a cascade of inflammation that permeates the entire brain, initiating its destructive course long before any memory loss becomes apparent.
NU-9 has demonstrated a potent ability to target and significantly reduce this specific subtype, underscoring its potential value in the earliest phases of Alzheimer’s disease, a period when therapeutic interventions are considered most effective. By curtailing the proliferation of this particular oligomer subtype, NU-9 may effectively prevent the detrimental activation of astrocytes.
While astrocytes serve as the brain’s primary defense mechanism, they can become destructive when driven into a reactive state. This detrimental activation can lead to synaptic damage, the release of pro-inflammatory molecules, and an acceleration of neurodegeneration. Halting this destructive astrocytic response, the researchers suggest, could represent one of the most impactful strategies for slowing the progression of Alzheimer’s disease.
Kranz and Silverman drew parallels between this therapeutic strategy and established early intervention approaches used in the prevention of other chronic diseases, such as cancer and heart disease. Professor Silverman offered an analogy: "Most people are used to monitoring their cholesterol levels. If you have high cholesterol, it doesn’t mean that you will have a heart attack soon. But it’s time to take drugs to lower your cholesterol levels to prevent that heart attack from happening down the road. NU-9 could play a similar role. If someone has a biomarker signaling Alzheimer’s disease, then they could start taking NU-9 before symptoms appear."
Professor Klein added to this vision, noting the ongoing development of early diagnostic blood tests for Alzheimer’s disease. He expressed that the convergence of improved early diagnostic capabilities with a drug capable of halting the disease’s progression represents the ultimate therapeutic goal.
The research team is currently undertaking further studies to evaluate NU-9 in additional Alzheimer’s disease models, including an animal model that more accurately reflects late-onset disease, which is more characteristic of typical human aging. Furthermore, the researchers intend to extend the observation period in their animal studies to ascertain whether symptoms ultimately develop in treated animals and to meticulously examine how early intervention with NU-9 influences memory function and neuronal health over extended periods. This research was supported by a grant (AG061708) from the National Institute of Health.
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