Who *isn't* afraid of Alzheimer's?

I have found microglia interesting to learn about in the past, and have written here, here, here, here, and here, about their proposed relationship to pain.

Yesterday I saw a news story about researchers in Germany who carefully studied the relationship between microglia and neurons undergoing Alzheimer-like changes in mice, Dangerous custodians: Immune cells as possible nerve-cell killers in Alzheimer's disease,
and was immediately intrigued.

An advance online publication of the paper, Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease, is freely accessible, at least for now.

That stressed neurons exude the chemokine, fractalkine, or that this substance attracts microglia, isn't fresh news. Like a bunch of little cellular opportunists, microglia catch the "scent" and begin moving toward it. Like any bunch of scavengers converging on a picnic, in this case, the amyloid-β forming and piling up, they also secrete/excrete (while gorging and multiplying, I suppose). What they signal/secrete/excrete isn't really explained, but what is news, is that it, or else just the sheer numbers of microglia converging, apparently sickens the affected neurons even more, kills them, according to this story.

In the paper, the authors, Fuhrmann etal., state,

"In Alzheimer's disease, microglia represent a double-edged sword. On the one hand, microglia can have a beneficial effect by secreting neurotrophic factors and phagocytosing amyloid beta (Aβ)², the latter of which remains controversial³. On the other hand, microglia may also be neurotoxic⁴. Little is known about the neurotoxic role of microglia in Alzheimer's disease. Human peripheral blood monocytes that are stimulated with Aβ induce neuron loss in vitro⁵. Neurons cultured without microglia are resistant to Aβ-induced neurotoxicity⁶."

The authors decided to interfere, genetically, with the receptors in the microglia that allow them to sense fractalkine; CX₃CR1,

"the unique receptor for fractalkine/CX₃CL1, which is expressed in neurons and presumably acts as a membrane-bound adhesion molecule and/or cleaved chemoattractant and is important for recruiting CX₃CR1-expressing microglia to injured neurons^{9, 10}."

They managed to show that it was definitely the microglia causing the neuron death, not any other factor. Furthermore, knocking out the ability of microglia to "smell" fractalkine didn't seem to interfere with their ability to clear the amyloid material associated with Alzheimer's. Moreover, the same treatment of the microglial receptor gives inconclusive results in other kinds of conditions - only in Alzheimer's does it seem to be a helpful intervention.

Supplementary information for this paper.

Fuhrmann, M., Bittner, T., Jung, C., Burgold, S., Page, R., Mitteregger, G., Haass, C., LaFerla, F., Kretzschmar, H., & Herms, J. (2010). Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease Nature Neuroscience DOI: 10.1038/nn.2511