Microglial Cells Shown to Play an Active Part in Alzheimer’s Development
A scientific team from the Institute for Regenerative Medicine of the University of Zurich, along with collaborators in the U.K. and the U.S., say they have demonstrated that dysfunctional microglial cells contribute to the loss of synapses in Alzheimer’s disease (AD) and other neurodegenerative diseases. These scavenger cells usually monitor the function of neurons in the brain by removing excess synapses during development or toxic protein aggregates. Until now, their role in neurodegenerative disorders has remained controversial, according to the researchers.
The researchers report their finding (“TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss”) in Neuron.
In an initial step, the investigators examined the effect that certain risk genes for AD have on the production of the β-amyloid peptide. They found no effect in neurons. This led the researchers then to examine the function of these risk genes in microglial cells, where they made a discovery: If they turned off the gene for the TDP-43 protein (a DNA–RNA binding protein encoded by the Tardbp gene) in these scavenger cells, these cells remove β-amyloid very efficiently. This is due to the fact that the lack of TDP-43 protein in microglia led to an increased scavenging activity (phagocytosis).
In the next step, researchers used mice, which acted as a disease model for AD. In this case, as well, they switched off TDP-43 in microglia and observed once more that the cells efficiently eliminated the β-amyloid. Surprisingly, the increased scavenging activity of microglia in mice led also to a significant loss of synapses at the same time. This synapse loss occurred even in mice that do not produce human amyloid. This finding that increased phagocytosis of microglia can induce synapse loss led researchers to hypothesize that perhaps, during aging, dysfunctional microglia could display aberrant phagocytic activity.
“Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results,” wrote the scientists. “Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.”
“Nutrient deprivation or starvation-like mechanism during aging could enhance phagocytic mechanism in microglia and this could lead to synaptic loss,” said Lawrence Rajendran, M.D., head of the Swiss lab.
The results show that the role of microglial cells in neurodegenerative diseases like AD has been underestimated. It is not limited to influencing the course of the disease through inflammatory reactions and the release of neurotoxic molecules as previously assumed.
Instead, this study shows that microglial cells can actively induce neurodegeneration. “Dysfunction of the microglial cells may be an important reason why many AD medications reduce the amyloid plaques in clinical testing, but the cognitive functions in patients do not lead to improvement,” added Dr. Rajendran.