A research team led by professor Wim Annaert (VIB/KU Leuven) has presented new insights into the roles of different γ-secretases in the development of Alzheimer’s disease (AD). γ-secretases are enzymes that contribute to the production of amyloid peptides that in AD aggregate in abnormal clusters, so-called ‘amyloid plaques’. These build up between nerve cells and disrupt brain communication. Postdoctoral researcher Ragna Sannerud from the team of professor Annaert together with several collaborators have focused on the slight differences between two types of γ-secretase. This has now led to a breakthrough that might open up new opportunities in the search for an Alzheimer’s disease (AD) treatment. This unexpected discovery underlines the importance of continued basic research.
The accumulation of short protein fragments between nerve cells in the brain is a known pathological hallmark of AD. These protein fragments are created by secretases, enzymes that cleave proteins into smaller pieces. One of the fragments that is produced following cleavage by the γ-secretase is the amyloid-β peptide, which aggregates to form amyloid plaques. The accumulation of amyloid plaques in the brains of AD patients leads to the gradual degeneration of neural networks.
Prof. Annaert: “Although γ-secretase is clearly involved in the development of AD, its therapeutic potential has been severely jeopardized by subsequent failures of clinical trials with inhibitors. The reason for these failures is that, even 20 years after its discovery, we still lack comprehensive knowledge of the function, structure and physiology of γ-secretase.”
A closer look at two types of γ-secretase
γ-secretases appear in slightly different forms, but the physiological relevance of this fact remained largely unknown until now. The study now demonstrates for the first time that these different types are active in different parts of the cell.
Prof. Annaert: “γ-secretases that contain a protein called presenilin2 are active in lysosomes, the compartments within the cell that are needed for degradation of cellular constituents. Hence, presenilin2-γ-secretase not only cleaves other types of proteins than the γ-secretases containing presenilin1, but because of this localization it generates a pool of intracellular Aβ, including the longer and more toxic forms of Aβ.”
Intracellular Aβ as a therapeutic avenue
Because it is present in relatively small amounts, as compared to the majority that is released from cells and neurons, intracellular Aβ has often been overlooked in terms of its relevance to AD development. Unjustly so, according to prof. Annaert.
Prof. Annaert: “Accumulation of intracellular Aβ is among the earliest signs when AD develops, evident even before the clinical manifestation of the disease. This discovery strongly supports the development of selective inhibitors for presenilin2-γ-secretase as a novel therapeutic avenue that will act at the heart of intracellular Aβ generation during disease onset, while leaving other important biological processes undisturbed.”
Unexpected find underlines the importance of basic research
Remarkably, it was completely unanticipated that the existence of slightly differently composed γ-secretases could contribute to two different pools of toxic Aβ species.
Prof. Annaert: “Taking into account the comments of colleagues, it was a surprise that such important novel roles for presenilins could still be discovered after 20 years of investigation. Particularly notable is that this could only be discovered through a basic research approach. It’s important to note that such research suffers strongly nowadays from a lack of sufficient financial support. The focus nowadays is predominantly on so-called translational research, but we tend to forget that basic research is still essential to understanding the molecular basis of disease onset, particularly in neurodegenerative diseases like AD.”
This study provides a foundation for the development of new cellular and in vivo disease models that will allow researchers to address the contribution of intracellular Aβ accumulation to AD development, particularly in the early stages, i.e. the moment that disease progression might still be halted or even reversed.
Prof. Annaert: “We have to be cautious however: these findings have been realized in cell cultures and need to be validated in proper in vivo models. However, for this to happen, it is essential that we first develop new mouse models on the basis of our findings. For the past 20 years, we have mostly used the same transgenic models. They have had their value in recapitulating certain features of the disease, but largely fail to provide insights into disease onset. With a proper understanding of how crucial disease-related proteins, like the different γ-secretases, are localized and regulated in neurons, we can now initiate the development of new models that might address the critical stages of disease onset. These, in turn, might provide the starting points for the development and testing of novel, selective presenilin2 γ-secretase inhibitors to halt the intracellular build-up of toxic peptides.”