While studying the genetic basis for Alzheimer’s disease, researchers from Vlaams Institute for Biotechnology (VIB-KU, Leuven, Belgium) have discovered that many genetic risk factors associated with Alzheimer’s affect microglia, and more particularly their response to amyloid-β.
Epidemiological studies have revealed that approximately two-thirds of a person’s risk for Alzheimer’s disease is genetically determined. Yet despite decades or research, the genetic basis of Alzheimer’s remains largely undefined. Though many risk genes have already been identified, recent evidence suggests that there could be hundreds of additional genetic variants that contribute towards the disease that are yet to be discovered.
Bart De Strooper (VIB-KU) commented: “Two crucial questions arise from the myriad of genetic studies. First, what is the link between these Alzheimer risk genes and the amyloid-β plaques or tau tangles we find in Alzheimer brains; and second, are they all involved in one central cellular or molecular pathway, or do they define many parallel pathways that all lead to Alzheimer’s?”
The team aimed to investigate when these genes are expressed and whether they respond to tau or amyloid-β pathology.
“To gain more insight, we checked gene expression in two different mouse models of Alzheimer’s, one displaying amyloid-β and the other tau pathology, at different ages,” explained Annerieke Sierksma (VIB-KU). “We identified that many of the genes linked to Alzheimer’s risk are particularly responsive to amyloid-β but not to tau pathology.”
The researchers discovered the genetic basis of microglial activation as they uncovered 11 new risk genes that are significantly up-regulated when exposed to increased levels of amyloid-β. All of these genes are expressed in microglia.
“We could confirm that microglia exposed to amyloid-β drastically switch to an activated status, something that occurs to a much lesser extent in the tau mice,” commented Ashley Lu (VIB-KU). “These new insights indicate that a large part of the genetic risk of Alzheimer’s disease involves the microglial response to amyloid-β.”
Commenting on the gene-based view for the disease, De Strooper observed: “One single genetic variant within a functional network will not lead to disease. However, multiple variants within the same network may tip the balance to a disease‐causing disturbance. Such a hypothesis could also explain the conundrum that some individuals with a lot of amyloid-β in their brain do not develop clinical symptoms.”
“While amyloid-β might be the trigger of the disease, it is the genetic make‐up of the microglia, and possibly other cell types, which determines whether a pathological response is induced,” added Mark Fiers (VIB-KU). “Identifying which genetic variants are crucial to such network disturbances and how they lead to altered gene expression will be the next big challenge.”
Sources: Sierksma A, Lu A, Mancuso R et al. Novel Alzheimer risk genes determine the microglia response to amyloid-B but not to TAU pathology. EMBO Mol. Med. doi:10.15252/emmm.201910606; www.vib.be/en/news/Pages/Alzheimer-risk-genes-converge-on-microglia.aspx