Researchers at Northwestern University have demonstrated further progress in early intervention against Alzheimer’s with the experimental drug NU-9. In a new study, they identified a previously unknown, highly toxic subtype of amyloid beta oligomers that triggers neuronal dysfunction, inflammation and immune cell activation at an early stage. NU-9 significantly reduced these oligomers, thereby mitigating damage in a mouse model of the disease even before symptoms such as memory loss appeared. The findings, published in Alzheimer’s and Dementia, point to a new strategy to combat and potentially prevent the disease in its early stages.

Alzheimer’s begins decades before visible symptoms, with the accumulation of toxic amyloid beta oligomers in neurons and glial cells, leading to inflammation. Many clinical trials fail because they start too late, when the pathology is already advanced. The Northwestern scientists simulated a presymptomatic phase by administering NU-9 orally over 60 days. The drug, a small molecule compound originally developed for amyotrophic lateral sclerosis (ALS), improved neuronal health by breaking down toxic protein aggregates and activating cellular repair mechanisms.

The study highlighted a specific oligomer subspecies, called ACU193+, which originates early in stressed neurons before migrating to astroycts. These stellate cells, which normally protect neurons and control inflammation, become reactive and harmful by the oligomers, which destroys synapses and accelerates neurodegeneration. NU-9 drastically lowered the binding of these oligomers to astroycetes, reduced reactive astrogliosis – a marker of neuroinflammation – and decreased abnormal forms of TDP-43 associated with cognitive impairment. These effects extended across multiple brain regions, indicating a broad anti-inflammatory effect.

Original Paper:

Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases | PNAS

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