. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

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  1. Both the Holtzman lab and our lab explored the role of microglia in mediating tau-induced neurodegenerative phenotypes in mice. Here, Shi et al. present exciting results of marked neuroprotection in a tau model after microglial ablation. In a different tau model, we did not observe strong changes in tau, astrocytic activation, or neurodegeneration markers following modest microglial reduction. In comparison, the Holtzman laboratory obtained a dramatic, near-total reduction of microglia with their treatment, likely due to differences in the PLX dose that was used, and possibly indicating a threshold phenomenon of microglia themselves that results in this protective effect.

    Congrats to the Holtzman lab on this intriguing observation. It will be fascinating to better understand how complex neuronal-glial interplay impacts neurodegeneration across multiple domains.

    View all comments by Bradley Hyman
  2. Dissecting the contribution of p-tau itself versus the innate immune system to neuronal loss in a model of tau pathology, this new study from the lab of David Holtzman showed that neuronal pathology and loss is almost exclusively driven by microglia. Moreover, the effect of ApoE on neurodegeneration is dependent on microglia, while absolute amount of ApoE is not the only key to neurodegeneration. Rather, the source and location of ApoE, in addition to the quantity, matters for neurodegeneration. The authors speculate that the effect of ApoE may predominantly result from regulating microglial function. Interestingly, depletion of microglia led to increased expression of ApoE in astrocytes and neuronal subtypes without affecting neuronal survival! This is in accordance with our study where we showed that ApoE upregulation associated with a highly dysregulated microglia phenotype in disease and with decreased neuronal survival. We and others confirmed that upregulation of ApoE expression also plays a role in human microglia in disease.

    When investigating microglia functionality in the neurodegenerative brain, we already showed that loss of homeostatic signature seems to be more important for microglia dysfunction than aberrant activation. This concept was supported by this study of Shi et al.: They found that the activation status, rather than the absolute number of microglia, is functionally associated with neurodegeneration. Although ApoE deficiency is promoting proliferation of microglia, Shi et al. could show that ApoE-deficiency preserved the homeostatic microglia signature and neuronal survival in their model of tauopathy, a key finding that we already identified in our study using different disease models.

    In conclusion, microglia are the driving force of neuronal loss in tauopathy. Moreover, ApoE’s effect on neurodegeneration is mediated almost exclusively by microglia. Therefore, restoring microglial function rather than lowering general amounts of ApoE in the brain might be a suitable therapeutic strategy in the future.

    View all comments by Susanne Krasemann
  3. Microglia and neuroinflammation play a central role in the pathogenesis of Alzheimer’s disease, as highlighted by several genome-wide association studies (GWAS). While the role of microglia has been extensively studied within the context of multiple Aβ models, there are still some discrepancies about their exact contribution to pathology. On one hand, partial ablation of microglia reduced synaptic pathology and attenuated cognitive deficits (Olmos-Alonso et al., 2016; Dagher et al., 2015; Spangenberg et al., 2016) and even prevented Aβ plaque formation (Sosna et al., 2018; Spangenberg et al., 2019). On the other hand, loss of function of TREM2 stopped microglial activation and exacerbated plaque pathology, suggesting that switching microglia on may be a potential strategy to clear Aβ (Parhizkar et al., 2019). 

    However, the link between microglia and tau-induced neurodegeneration has remained elusive, until now. Both Holtzman's and our lab explored independently the role of microglia in tau pathology using two complementary approaches, resulting in either almost complete or only partial depletion (Mancuso et al., 2019) of microglia in mice overexpressing the human P301S mutated tau gene. Overall, our studies show that ablation of microglia using colony-stimulating factor-1 receptor (CSF1R) inhibitors reduced tau phosphorylation and aggregation, and preserved neurons. Interestingly, these effects were achieved not only by reducing microglial numbers but also by pushing cells into a homeostatic phenotype.

    This clearly indicates that microglial activation is a driving force of neuronal death in tauopathy. While it is encouraging to see that both our and the Holtzman labs’ results go in the same direction, they suggest a bit of a conundrum if we were to develop treatments targeting microglia for Alzheimer’s disease. Under the assumption that microglia are beneficial in the context of amyloid pathology (despite strong controversy around this aspect), boosting microglia to clear plaques will exacerbate tau pathology and neuronal death. 

    References:

    . 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.

    . CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice. Brain. 2019 Oct 1;142(10):3243-3264. PubMed.

    . 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.

    . Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci. 2019 Feb;22(2):191-204. Epub 2019 Jan 7 PubMed.

    . Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nat Commun. 2019 Aug 21;10(1):3758. PubMed.

    . 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.

    . 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.

    View all comments by Renzo Mancuso

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  1. In Tauopathy, ApoE Destroys Neurons Via Microglia