Microglia Plays Crucial Role in Early Progression of Alzheimer’s Disease

For the first time, researchers have determined how toxic tau fibrils spread by the help of brain immune cells called microglia during the early stages of Alzheimer’s disease (AD). The discovery of this new pathway may lead to a therapeutic target for AD, one that has not been previously identified.

In patients with AD, the gradual decline in cognitive function and loss of neurons is preceded by the harmful build-up of the protein tau in the brain. Tau accumulates as tiny fibers called fibrils in brain regions that are critical for learning and memory. But how they spread during the early stage of AD was previously unknown.

“This study found that tau can be carried from one neuron to another by the brain’s own immune cells in a process that may contribute to the progression of AD,” explained corresponding author Tsuneya Ikezu, MD, PhD, professor of pharmacology & experimental therapeutics and neurology at Boston University School of Medicine.

The findings appear online in the journal Nature Neuroscience.

One important function of microglia is to constantly survey the brain environment for sensing and clearing damage and infection. For this purpose, microglia actively engulf dead cells, debris, inactive synapses or even unhealthy neurons. Then, to transfer signaling molecules and present antigen to activate an immune response, microglia release nano-scale particles called exosomes, which can be taken up by other cells.

The researchers hypothesize that in an early stage of AD brain, microglia may spread the harmful protein tau by taking up tau-containing fibrils and then releasing them via the exosomes, which can be absorbed by nearby neurons.

Image shows microglia and neurons.
One important function of microglia is to constantly survey the brain environment for sensing and clearing damage and infection. For this purpose, microglia actively engulf dead cells, debris, inactive synapses or even unhealthy neurons. Image is for illustrative purposes only. Credit: GerryShaw.

Using an experimental model, the researchers found that pharmacologic depletion of microglia suppressed the spread of tau from one brain region to another. The depletion of microglia also restored the neural excitation, which is affected by the spread of tau. They also found that pharmacologic inhibition of exosome production suppressed the tau spread in the brain.

“Our results using an experimental model of AD suggest that microglia could facilitate the spread of tau fibrils between neurons by releasing tau-containing exosomes. This finding indicates that molecules involved in exosome release by microglia has a great potential as novel therapeutic targets to prevent the progression of AD,” added Ikezu.

About this Alzheimer’s disease research

Funding: Funding for this study was provided in part by grants from Alzheimer’s Association, Alzheimer’s Art Quilt Initiative, Boston University Alzheimer’s Disease Center, BrightFocus Foundation and Coins for Alzheimer’s Research Trust.

Source: Gina DiGravio – Boston University Medical Center
Image Source: The image is credited to GerryShaw and is licensed CC BY-SA 3.0
Original Research: Abstract for “Depletion of microglia and inhibition of exosome synthesis halt tau propagation” by Hirohide Asai, Seiko Ikezu, Satoshi Tsunoda, Maria Medalla, Jennifer Luebke, Tarik Haydar, Benjamin Wolozin, Oleg Butovsky, Sebastian Kügler and Tsuneya Ikezu in Nature Neuroscience. Published online October 5 2015 doi:10.1038/nn.4132


Abstract

Depletion of microglia and inhibition of exosome synthesis halt tau propagation

Accumulation of pathological tau protein is a major hallmark of Alzheimer’s disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus–based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.

“Depletion of microglia and inhibition of exosome synthesis halt tau propagation” by Hirohide Asai, Seiko Ikezu, Satoshi Tsunoda, Maria Medalla, Jennifer Luebke, Tarik Haydar, Benjamin Wolozin, Oleg Butovsky, Sebastian Kügler and Tsuneya Ikezu in Nature Neuroscience. Published online October 5 2015 doi:10.1038/nn.4132

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