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Sosna J, Philipp S, Albay R 3rd, Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM, Glabe CG. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol Neurodegener. 2018 Mar 1;13(1):11. PubMed.
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University of Southampton
This is an interesting study, expanding recent literature on the therapeutic potential of CSF1R targeting in AD (Olmos-Alonso, 2016; Dagher et al., 2015; Spangenberg et al., 2016).
Here, a preventative treatment with a CSF1R inhibitor was applied, in order to deplete microglia before the formation of neuritic plaques. Surprisingly, depletion of microglia caused an unexpected impairment of amyloid levels, leading to a mild improvement in some behavioral tests. These results are interesting because they provide an additional line of evidence for the beneficial impact of targeting microglial numbers in AD, but also a bit puzzling because, after all, it is difficult to understand how Aβ production could have been “switched-off” in a transgenic model where the promoters are not microglia or CSF1R-dependent. Data analyzing the levels of APP expression and/or protein levels of Aβ could have clarified this issue, alongside analysis of the proteins involved in APP processing.
Also, if the intervention was indeed so effective in arresting the formation of amyloid pathology, one would have expected a complete prevention of the behavioral deficits (as this is a preventative approach), but this is not observed here as cognitive tests such as the Y-maze or elevated plus maze did not evidence any significant improvement.
Therefore, the understanding of the mechanistic link of pre-pathology CSF1R inhibition and pathology is somehow missing, and the extrapolation of these results to the preventative value of CSF1R blockade in AD must be with interpreted with caution.
References:
Olmos-Alonso A, Schetters ST, Sri S, Askew K, Mancuso R, Vargas-Caballero M, Holscher C, Perry VH, Gomez-Nicola D. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology. Brain. 2016 Mar;139(Pt 3):891-907. Epub 2016 Jan 8 PubMed.
Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, West BL, Green KN. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation. 2015 Aug 1;12:139. PubMed.
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, West BL, Green KN. Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain. 2016 Apr;139(Pt 4):1265-81. Epub 2016 Feb 26 PubMed.
View all comments by Diego Gómez-NicolaIndiana University School of Medicine
The authors present an intriguing study that highlights the interplay between microglia and neurons in the progression of amyloid pathology in a mouse model of Alzheimer’s disease. Although others have demonstrated that early intervention with CSF1R inhibitors staves off neuronal loss, this study expands on the critical role microglia play in the progression of pathology.
The authors report a remarkable reduction in plaque burden and intraneuronal Aβ after three months of PLX3397 treatment. One of the difficulties with the manuscript arises from the use of PLX3397 to ablate microglia, since it inhibits CSF1R/kit found both on microglia and in a subset of neurons. Thus, it is not possible to determine if the observed effects on pathology arise from salutary effects of the drug on neurons or from the loss of microglia in the brain. Surprisingly, no analysis on neuron number was done, which would be informative as to the impact of PLX3397 on neuronal health. This is an important aspect to understand, as it feeds into the authors’ proposal of plaques deriving from dying neurons.
Although PLX3397 effectively reduces the number of microglia and plaques in the brain, it is puzzling that the remaining plaques still have high microglia coverage, as the authors note in the discussion. These resilient microglia are engaged with the plaque surface, and raise the question of why they have become CSF1-independent for their survival.
The study also implies that ablation-resistant microglia may be endowed with beneficial pathology-modifying effects that depletion therapies could harness. Microglial ablation strategies should be employed cautiously in a translational setting, since it is unknown if any detrimental side effects arise following long-term ablation. Indeed, mice and humans with loss-of-function CSF1R mutations have a broad range of pathological phenotypes.
Overall this paper highlights some exciting ideas; however, it falls short on the delivery of clear results implicating microglia in the observed phenotypes and behavioral improvement.
View all comments by Gary LandrethUniversity of Munich (LMU)
I am puzzled by this experimental observation of supposedly beneficial effects of interference with CSF1-R function given the clinical syndrome of HDLS/POLG, a dementing condition due to CSF1-R loss-of-function mutations (e.g., Pridans, et al. 2013). What may be possible explanations that could perhaps reconcile these two apparently opposite effects of CSF1-R?
References:
Pridans C, Sauter KA, Baer K, Kissel H, Hume DA. CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function. Sci Rep. 2013 Oct 22;3:3013. PubMed.
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