Overzealous Microglial Cells May Be Responsible For The Neurodegeneration Seen In Alzheimer’s

For the first time in existence, scientists have been able to illustrate an effect of the scavenger cells of our brain, the microglia, which will take you by surprise. If the microglia lack a protein by the name of TDP-43, not only will these brain cells remove the notorious Alzheimer’s plaques but they will also destroy synapses.

Like most neurodegenerative diseases, Alzheimer’s patients also exhibit a continuing deterioration of their cognitive abilities. This is due to the progressively increasing synapse loss, the meeting point of neurons in the brain. When it comes to Alzheimer’s, it is β-amyloid protein fragments that rank high in our suspect list for the death of neurons. β-amyloid peptides will cluster together and produce those characteristic Alzheimer’s plaques.

According to a study published in Neuron, researchers from the University of Zurich are now able to demonstrate that malfunctioning microglial cells are involved in the loss of synapses in not only Alzheimer’s but also other neurodegenerative disorders. Microglia usually track the functioning of our neurons by getting rid of surplus synapses produced in development as well as harmful protein aggregates that could be toxic to the brain. Before this, the role of microglia in association with neurodegeneration has always been controversial.

Initially in the study, the researchers tried to determine what impact certain genes that carry a risk for Alzheimer’s have on β-amyloid peptide production. Examining the function of these Alzheimer’s risk genes in neurons, they found no impact. This caused them to start examining microglial cells, leading to a discovery- if they turned off the gene responsible for TDP-43 protein production in microglia, the scavenger cells would get rid of β-amyloid with greater efficiency. This is because a lack of the TDP-43 protein causes an increase in the phagocytic activity, i.e. the scavenging abilities, of the microglia.

The researcher’s then proceeded to use mice, where once again they turned off the TDP-43 production in mice microglia. They were able to discover that not only did the scavenger cells effectively remove the β-amyloid, astonishingly, the boosted scavenging competencies of microglia caused mice to lose a significant amount of synapses as well. This has led the researchers’ to hypothesize that maybe once we age, dysfunctional scavenger cells maybe exhibiting deviant phagocytosis.

What Does This Mean?

What the results exhibit is that the role of microglia in regards to neurodegeneration seen in Alzheimer’s has been profoundly underestimated. Microglia aren’t only restricted to inflammatory processes and neurotoxic molecule release in the course of Alzheimer’s as previously conjectured. According to the researchers, this dysfunction noted in our microglia may be a crucial reason as to why during clinical testing, Alzheimer's drugs decrease β-amyloid plaques but the patient's cognitive abilities do not improve.

Citations

1. Rosa C. Paolicelli, Ali Jawaid, Christopher M. Henstridge, Andrea Valeri, Mario Merlini, John L. Robinson, Edward B. Lee, Jamie Rose, Stanley Appel, Virginia M.-Y. Lee, John Q. Trojanowski, Tara Spires-Jones, Paul E. Schulz, Lawrence Rajendran. TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron, 2017; DOI: 10.1016/j.neuron.2017.05.037