Rethinking Alzheimer’s disease with brain-on-chip technology.

Neurogenerative diseases such as Alzheimer’s disease remain among the most difficult to study, with many clinical trials ending in failure and effective therapies remaining elusive. One reason for this is the lack of physiologically relevant models that can faithfully replicate the complexity of the human brain. Additionally, our understanding of the intricate pathology involved in neuronal degeneration is still evolving.

For many years, Alzheimer’s research has centered on the amyloid plaque hypothesis, which suggests that the accumulation of amyloid-beta plaques in the brain is a central driver of disease development. This has prompted widespread efforts to target these plaques. But even with the development of potent antibodies, clinical outcomes have been limited.

As the field evolves, attention is shifting toward other potential drivers of Alzheimer’s disease, particularly the role of soluble amyloid-beta oligomers.

The soluble amyloid-beta oligomer hypothesis

Emerging research suggests that at the very early stages of Alzheimer’s disease, soluble amyloid-beta oligomers start to accumulate in the brain, long before the formation of amyloid plaques. These oligomers are believed to be extremely toxic to neurons and other cell types within the brain, potentially leading to disease onset and progression. As a result, strategies to remove these oligomers or limit their toxicity are emerging as promising therapeutic avenues.

Exploring this theory requires the use of models that more accurately represent the cellular architecture and microenvironment of the human brain. While traditional 2D cultures and animal models have their place, they often fall short in their ability to translate findings into clinically relevant insights.

Next-generation modeling with brain-on-chip technology

Organ-on-chip systems have emerged as a compelling alternative, offering a more dynamic and physiologically relevant context for studying disease mechanisms and evaluating novel treatments. In particular, brain-on-chip devices integrate various human brain cell types—such as neurons, astrocytes, and endothelial cells—with compartmentalized microfluidic environments that mimic the brain’s structure and function. These systems allow researchers to model complex processes such as synaptic activity, neurotoxic spreading, and drug responses with greater accuracy than conventional models.

ETAP-Lab’s integrated approach

One company working at the forefront of this space is ETAP-Lab, a contract research organization with expertise in neurodegenerative disease modelling. Through a collaboration with microfluidics specialist NETRI, ETAP-Lab has developed brain-on-chip models tailored to major neurodegenerative conditions such as Alzheimer’s, Parkinson’s, and Amyotrophic Lateral Sclerosis.

At the core of this innovation is their method for producing stable misfolded tau oligomers (TauO) from recombinant full-length human tau protein. Unlike conventional approaches, this technique requires no chemical modification or helper proteins, resulting in highly physiologically relevant neurotoxins for disease modeling. The team utilizes Revvity’s Operetta™ CLS high-content analysis system to quantify cellular responses to neurotoxins and pharmacological treatments. By combining high-throughput screening methods and automated microscopy in a microplate format, they can assess the neurotrophic, neuroprotective, or neurotoxic effects of numerous chemical compounds in a controlled, reproducible, and automated manner.

If you’re interested in how ETAP-Lab is applying these innovations to better understand early neurodegenerative mechanisms—and what this could mean for future drug development—read our exclusive interview with ETAP-Lab’s CEO, Nicolas Violle.