. 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.

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  1. The role of microglia in amyloid generation/removal appears to be very complex. The authors now present clear data that the presence of microglia is required to allow amyloid plaque deposition. We favor their argument that microglia may secrete factors that facilitate Aβ fibrillization. The authors nicely demonstrate that in the absence of microglia, dense core amyloid plaques have 50–70 percent less ApoE, which is in good agreement with our recent findings in TREM2 loss-of-function mice (Parhizkar et al., 2019). It may be that the absence of microglial ApoE (or other seeding factors released from microglia such as ASC specks (Venegas et al., 2017)) reduces amyloidogenesis and therefore prevents plaque deposition and compaction.

    Our longitudinal amyloid-PET-imaging experiments also revealed an increased fibrillar amyloidogenesis early during pathogenesis in APPPS1/Trem2−/− mice at 3 and 6 months, which leveled out during late disease progression at 12 months of age. This could have been due to the failure of mutant microglia to cluster around plaques and to increase ApoE expression (or other factors driving amyloid plaque compaction and growth). Nevertheless, one should be careful comparing total microglial absence with TREM2 loss-of-function mutants, because the latter selectively target a microglia population with a disease-associated signature but leave homeostatic microglia intact (Krasemann et al., 2017; Keren-Shaul et al., 2017). 

    References:

    . 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. Correction.

    . Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature. 2017 Dec 20;552(7685):355-361. PubMed.

    . The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017 Sep 19;47(3):566-581.e9. PubMed.

    . A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.

    View all comments by Samira Parhizkar
  2. This nice study by Green’s group investigates what happens after elimination of microglia in the 5xFAD mouse model. The hypothesis they propose, i.e., that microglia take up Aβ and form fibrils, is interesting but not novel. Wisniewski and others came to a similar conclusion many years ago (e.g. Wisniewski et al., 1990; Frackowiak et al., 1992; for more references see Stalder et al., 1999). We previously reported that eliminating microglia in the APPPS1 mouse model for four weeks does not inhibit amyloid plaque formation, and I wonder whether the difference is the aggressiveness of that model (Grathwohl et al., 2009). APPPS1 mice have heavy Aβ42-driven pathology and carry a PS1 mutation, which in humans causes one of the earliest onsets of AD. Thus, in an aggressive model the microglia may play less of a role in deposition compared to a less aggressive model.

    To me, the most fascinating point is the increase in CAA. The role of microglia in cerebral β-amyloidosis is undisputed but it may be related to the recent discovery of microglia heterogeneity, because there is also mechanistic heterogeneity in amyloid fibril formation. Knocking out one pathway of amyloid deposition may cause another one to become more active. Interestingly, the equivalent amounts of total Aβ in PLX562-treated vs. non-treated animals suggest that microglial ablation shifts Aβ from the parenchyma to the vasculature, where it is then presumably deposited. Quite possibly, vascular amyloid could be more damaging to the human brain than parenchymal plaques, in which case microglial seeding of parenchymal deposits would be protective. Vascular amyloid can be prevented by early reduction of Aβ (Schelle et al., 2019). 

    References:

    . Ultrastructure of the cells forming amyloid fibers in Alzheimer disease and scrapie. Am J Med Genet Suppl. 1990;7:287-97. PubMed.

    . Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol. 1992;84(3):225-33. PubMed.

    . Association of microglia with amyloid plaques in brains of APP23 transgenic mice. Am J Pathol. 1999 Jun;154(6):1673-84. PubMed.

    . Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia. Nat Neurosci. 2009 Nov;12(11):1361-3. PubMed.

    . Early Aβ reduction prevents progression of cerebral amyloid angiopathy. Ann Neurol. 2019 Oct;86(4):561-571. Epub 2019 Aug 19 PubMed.

    View all comments by Mathias Jucker
  3. This latest work from Kim Green’s laboratory shows that prolonged microglia depletion in 5xFAD mice (a common mouse model for AD) greatly reduces plaque formation, thus confirming recent findings by another group (Sosna et al., 2018). Notably, this phenomenon occurs when microglia are depleted before plaques begin to form (around 3–4 months of age). However, if the depletion starts after plaque formation, no obvious change in plaque load can be observed (Spangenberg et al., 2016). Together, these data suggest that microglia are critical for plaque deposition, at least at the early stages of disease.

    These studies will probably raise a lively debate. One may intuitively interpret these findings as a demonstration that microglia are primarily detrimental during amyloid pathology. However, the current paradigm identifies the soluble Aβ (especially oligomers) as the most neurotoxic form, whereas fibrillar Aβ is considered relatively benign. According to this view, fibrillization and subsequent deposition of soluble Aβ would reduce the bioavailability and diffusion of the most toxic Aβ species. Alongside the reduced plaque burden, Green’s data show an aggravated CAA (cerebral amyloid angiopathy), increased dystrophic neurites, and higher APP levels in 5xFAD mice with depleted microglia, as compared with non-depleted 5xFAD. Additionally, microglia depletion did not alter the production of soluble Aβ fraction, and no change could be seen at the learning and memory tests.

    Taken together, while microglia may be truly important for the formation of amyloid plaques, it remains to be determined if microglia depletion may represent a promising therapeutic strategy for AD.  Overall, the full picture of the role of microglia in AD may be more complicated than the idea that microglia are simply “beneficial” or “detrimental.” This work by Green’s laboratory certainly opens new perspective on the mechanisms of Aβ aggregation and plaque deposition.

    References:

    . 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.

    . 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 Simone Brioschi

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