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Targeting microglia in the fight against Alzheimer's disease
Alzheimer's disease (AD) is a complex, progressive neurodegenerative disorder that affects millions of people worldwide. The World Health Organization predicts a tripling of cases by 2050, highlighting the urgent need for new treatments. Microglia, the immune cells of the brain, express many gene variants that increase the risk of developing Alzheimer’s disease. The labs of Renzo Mancuso (VIB-Center for Molecular Neurology), and Bart De Strooper (VIB-KU Leuven Center for Brain and Disease Research), in collaboration with Janssen Pharmaceutica, now show how antisense nucleotides can target these cells in the brain. Their work appeared in the journal Molecular Neurodegeneration.
What if we focused on modulating microglia in Alzheimer’s disease?
Our brain is not made of neurons alone. Microglia, the professional immune cells of the brain, play a pivotal role in maintaining brain health and they are quick to respond when something goes wrong. More and more, research implicates malfunctioning microglia in neurodegenerative conditions such as Alzheimer’s disease. Strikingly, some of the strongest gene variants that confer risk for Alzheimer’s disease – such as APOE and TREM2 variants – are enriched or exclusively expressed in microglia.
Then what if we focus on microglia as a target for interventions against Alzheimer’s?
That is what the teams of Renzo Mancuso (VIB-University of Antwerp) and Bart De Strooper (VIB-KU Leuven) did, together with colleagues from Janssen Pharmaceutica.
More specifically, the researchers used antisense oligonucleotides (ASOs), or small strands of DNA that bind to a specified sequence of mRNA. In doing so, these ASOs can change gene expression by preventing the mRNA transcript from being translated into a protein. Put simply, they can put a brake on the processes that lead from DNA to protein.
ASO treatment changes microglia function, opening up exciting research and therapeutic avenues.
The idea worked.
In both cultured human microglia and mice with xenografted human cells, the ASOs – which showed a great safety profile – found their intended targets and they downregulated the expression of APOE and TREM2. This downregulation lasted for at least four weeks.
As a result of the downregulation of these genes, the microglia changed their gene expression and response to the presence of amyloid plaques. The plaques themselves, however, were not affected. In other words, the therapeutic relevance of these ASOs and the resulting downregulation of risk gene variants remains to be investigated.
Overall, this proof-of-concept study shows that ASOs are a safe, accurate, and effective way to change the expression of genes involved in Alzheimer’s disease and other neurodegenerative disorders.
Publication
Vandermeulen, Geric, et al. Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer’s disease. Molecular Neurodegeneration, 2024.
Funding
This work was funded by VLAIO, the European Research Council, the FWO program, the Methusalem grant, the Belgian Alzheimer Research Foundation (SAO-FRA), the Alzheimer’s Association USA, and the BrightFocus foundation.
Gunnar De Winter
