Alzheimer’s research needs a new theoretical framework

17 May 2016
According to Bart De Strooper (VIB/KU Leuven), it is unlikely that molecular genetics or molecular cell biology will continue to broaden our understanding of Alzheimer’s disease (AD) the way it has done over the last twenty years. He argues that AD research needs a more holistic approach to propel itself into the complex biology of the 21st century.

You state that the neuron-centric view of contemporary AD research needs to be expanded. Why is that?
Bart: “For over 20 years now, the ‘amyloid cascade hypothesis’ has been the main theoretical construct for AD. It proposes amyloid plaques – or their major constituents, the Aβ-peptides – as the direct cause of progressive neurodegeneration.

Although this biochemical approach has led to a tremendous increase in knowledge of the molecular biology, pathophysiology and diagnosis of AD, we need to go beyond in vitro research that is limited to evolved stages of the disease. The brain harbors an incredible variety of cell types, so in order to really understand AD, biochemical findings need to be integrated into the brain’s complex cellular context.”

In other words: AD research needs to ‘zoom out’ and take a wider scope?
“Yes, and not just in one way. First of all, many different cell types – and their interactions with one another – all contribute to the gradual evolution of AD. Microglia, astroglia and
oligodendrocytes, for instance, all contribute to a complex cellular phase of the disease. Hence, all of these cell types need to be taken into account.

Secondly, this cellular phase evolves over decades, so we also need to widen the temporal scope. AD starts insidiously many years before full dementia becomes apparent, but the amyloid cascade hypothesis provides no explanation for this silent incubation period.

And, lastly, advances in the field of single-cell biology have demonstrated the startling heterogeneity of the brain. This means we can’t just study random pieces of brain tissue. We need to widen the ‘spatial scope’ as well and add cellular resolution to the analysis instead of the bulk approach which is typical of the systems biology approaches at the moment.”

Taking the cellular, temporal and spatial aspects of the disease process into account seems like a daunting task.
“The brain is the most complex structure of the human body, so it’s definitely not an easy feat. Still, the enormous complexity can only be understood if the many separate findings of exploratory science are integrated into a broader conceptual framework than provided by the amyloid hypothesis. AD research clearly needs an ‘atlas’, so to speak, that encompasses the many parallel processes that go astray in the brains of AD patients.”

How would such an atlas be constructed?
“It could be generated by measuring all changes in the different cell types over different stages in a few relevant brain areas. The incredible progress in genome wide approaches at the single cell level of the last three years starts to make this a feasible aim.”

What do you hope to achieve with this review article?
“I mainly hope that it stirs up the debate. I am convinced that a new integrated conceptual framework could transform the field, as it would be easier for AD researchers to appreciate and cross-pollinate each other’s work.

Such a framework would also provide a scientifically coherent basis for targeted therapeutics that address the different elements of the disease in a stage-dependent manner. If the AD research community agrees on that, we can start looking for a systematic way to realize the framework.”

You recently showed the relevance of G protein- coupled receptor 3 (GPR3) for AD. Can you elaborate?
“Indeed, together with Amantha Thathiah, we recently identified GPR3 as a therapeutic target for AD. The loss of GPR3 reduced amyloid burden and improved cognition in four AD mouse models. We also evaluated the GPR3 expression in post-mortem brain tissue from two cohorts of AD patients. These studies revealed that GPR3 expression is elevated in a subset of AD patients and is associated with disease progression. Given the vast resources required to develop and evaluate a new therapy, demonstrating the relevance of research findings in multiple disease-relevant models is crucial. Our research provides exactly this level of validation.”

Huang et al., Science Translational Medicine 2015
De Strooper and Karan, Cell 2016

Bart De Strooper (VIB/KU Leuven)