Depleting Microglia Prevents Amyloid-Beta Plaque Formation
By Jamie Talan
October 3, 2019
Article In Brief
Deleting microglia early in the disease process in animal models of Alzheimer's disease led to the prevention of amyloid plaques in the regions of the brain where microglia were eliminated.
Depleting microglia in animal models of Alzheimer's disease (AD) prevented the accumulation of amyloid plaques in the parenchymal space.
The finding, reported August 21 in Nature Communications, is part of a growing body of evidence implicating the involvement of microglia in the AD process.
The team, led by Kim Green, PhD, associate professor and vice chair in the department of neurobiology and behavior at the University of California, Irvine, wanted to understand the relationship between microglia and amyloid-beta (Abeta) plaque formation. Reactive astrocytes and activated microglia are commonly seen surrounding amyloid plaques.
A few years ago, the California scientists developed a colony stimulating factor 1 receptor (CSF1R) inhibitor that triggers a suicidal cascade in microglia, and this has allowed them to study the role these inflammatory cells play in many diseases.
Initially, they reported that deleting microglia in AD mice in the advanced stages of disease did not alter Abeta levels or plaque load but did lead to strong pathological effects, including less dendritic spine loss and significantly less neuronal cell loss. The animals also showed improvements in memory tests.
In their most recent studies in Nature Communications, they reported that deleting microglia early in the disease process—treating the animals during the first six months of life—led to the prevention of amyloid plaques in the regions of the brain where microglia were eliminated.
“We want to know how microglia facilitate the formation of amyloid-beta plaques,” said Dr. Green. “There are good things and bad things that microglia do, and we are now understanding that they are disease-stage specific and timing is critical.”
Study Methods, Findings
The scientists developed a potent oral CSF1R inhibitor, PLX5622, and administered it (in the feed) to 5xFAD mice for the first six months of life. Microglia are dependent on CSF1R signaling for their survival. The inhibitor knocked out about 90 percent of microglia in the first three days with no ill effects, and the inhibitor continued to keep microglia levels extremely low throughout the study period.
PLX5622 was designed to deplete microglia. This enables scientists to see whether Abeta would still accumulate without microglia present. In the first experiment, they fed a PLX5622-formulated chow to 5xFAD animals and their wild-type (normal) littermates beginning at 1.5 months old. The 5xFAD transgenic animals begin to show Abeta pathology by three months. The diet continued over a ten week or 24-week period.
The treatment wiped out 97 percent of microglia. Even at 24-weeks, the wild-type mice did not show any behavioral changes despite very small numbers of microglia. Genes normally expressed in microglia were also way down. The team reported that elimination of microglial prevented plaque formation in a number of areas in these animals.
Plaques found were always around surviving microglia, which were primarily found in the retrosplenial cortex and the thalamus.
The research team also studied gene expression in the surviving microglia and found that a number of genes were overexpressed. These genes have been linked with disease-associated microglia. Neither AD pathology nor the depleted levels of microglia had effects on AD-related genes. No changes in gene expression without microglia around could explain the reduced numbers of plaques.
Surprisingly, in the absence of microglia, the researchers documented an abundance of Abeta inside the cortical blood vessels in the 5xFAD mice, akin to cerebral amyloid angiopathy (CAA). This vascular deposition of Abeta caused thalamic microbleeds in a small number of the mice. (These bleeds are characteristic in CAA.)
Microglia could be “secreting factors that facilitate Aβ fibrillization, physically forming plaque cores from extracellular Aβ via compaction, or ingesting, aggregating, and modifying extracellular Aβ internally,” the scientists wrote in the paper.
Dr. Green said that PLX5622 is a tool that will help scientists understand the interaction between microglia and disease states. Identifying the mechanisms by which microglia facilitate plaque formation will allow for the development of more targeted therapies that could one day prevent the disease.
“In humans, we don't want to get rid of all microglia but we might be able to find ways to stop microglia” from kickstarting the disease process, he explained. He added that they also have to figure out why Abeta was now sticking in the vessels.
“The paper presents convincing data that microglia play a key role in facilitating the conversion of amyloid-beta monomers to ‘aggregates’ or ‘seeds’ which instigate amyloid plaque formation,” said David M. Holtzman, MD, FAAN, the Andrew B. and Gretchen P. Jones professor and chairman of the department of neurology at Washington University School of Medicine. “It suggests either that the process of amyloid-beta seeding occurs in microglia or that microglia secrete things or interact with other cells to allow amyloid-beta seeding. Very similar results were published by Charles Glabe and his colleagues at the University of California, Irvine last year.
“While elimination of microglia had no effect on amyloid plaques once plaques had already formed, these two papers clearly show a key role for microglia in amyloid-beta plaque formation. Kim Green's lab has also found that microglial elimination after plaque formation does not affect amyloid at that point; however, it does decrease the damage around amyloid. It will be very interesting to see the effects of eliminating microglia on the more severe neurodegeneration that occurs in the setting of other protein aggregates as occurs with tauopathy and synucleinopathy.”
Mathias Jucker, PhD, professor at the Hertie Institute for Clinical Brain Research at the University of Tübingen, said that the most interesting finding is that there was an increase in CAA. “Knocking out one pathway of amyloid deposition may cause another one to become more active.” He said it is possible that the vascular amyloid could be more damaging then the plaques in the parenchyma.