Benchmarking and validating a new organoid model of Alzheimer’s disease

Experimental research on Alzheimer´s disease (AD) relies heavily on mouse models, but these models poorly mimic human AD, leading to over 99% AD drugs failures in human trials. Consequently, there is an urgent need for more human-relevant experimental models of AD.

However, the use of alternative human cell models is constrained due to the complex 3D multi-cellular nature of AD pathology, including an inflammatory component.

In addition, their superiority over animal models remains uncertain, combined with insufficient validation regarding their relevance to human disease.

To overcome this, we propose to benchmark a human forebrain organoid model of AD carrying amyloidogenic APPNL-G-Fmutations in co-culture with isogenic microglia immune cells.

These organoids produce neurotoxic amyloid beta (Aβ), a hallmark of AD, and unlike AppNL-G-F mice they also produce hyperphosphorylated Tau protein, a second hallmark of AD.

We will use a transcriptomic approach to ask: 1) are these organoids in any way superior to correspondingAppNL-G-F mice? 2): how well do they overlap with human AD pathology? And 3) are they functional in response to the amyloid-lowering drug Aducanumab?

Answering these questions would give the first benchmarked and disease-validated AD organoid model and will be an important step towards promoting organoids’ wider use in AD research, thereby reducing the heavy reliance on mice while enhancing human relevance.