. Natural genetic variation determines microglia heterogeneity in wild-derived mouse models of Alzheimer's disease. Cell Rep. 2021 Feb 9;34(6):108739. PubMed.

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  1. This new, exciting study from the Howell lab unveils an interesting correlation between wild-derived mouse genetic variants and their microglia profile in the APP/PS1 model of amyloid pathology. While microglia in B6.APP/PS1, CAST.APP/PS1, and PWK.APP/PS1 mice exhibited similar progressions from a homeostatic state to disease-associated microglia (DAM) during amyloid pathology, microglia in WSB.APP/PS1 mice largely persisted as homeostatic population without a significant increase in DAM.

    One interesting challenge is to understand the causal relationship between mouse genetic variants and diverse microglia responses in amyloid pathology. Since genetic variations impact the progression of amyloid pathology, diverse microglia responses may be secondary to a different degree of pathology itself. Howell’s lab has shown in a previous study that Aβ accumulation and neuronal loss are higher in CAST.APP/PS1 and WSB.APP/PS1 than B6.APP/PS1 mice at 6 months of age (Onos et al., 2019). Moreover, cerebral amyloid angiopathy (CAA) was observed exclusively in the CAST.APP/PS1 and WSB.APP/PS1 cohorts, and the latter strain partially lost cerebrovascular integrity. Conversely, no neuronal loss or CAA occurred in B6.APP/PS1 mice at the same age. Such pathological differences, which may further increase at 9 months of age, which is when the authors performed the scRNA-Seq for this study, can drive the different signatures of microglia clusters in CAST.APP/PS1 and WSB.APP/PS1 versus B6.APP/PS1 mice.

    Conversely, it is also possible that the unique microglia profile of WSB.APP/PS1 mice, particularly the lack of DAM signature, may be primarily responsible for the severe pathology observed in this strain. Supporting this possibility, total Iba1+ myeloid cell numbers in WSB.APP/PS1 and CAST.APP/PS1 are significantly lower than in B6.APP/PS1, even if the latter strain has less amyloid pathology (Onos et al., 2019). This may indicate that WSB.APP/PS1 mice fail to generate a protective microglial response. CAST.APP/PS1 mice are also unique because, despite a global reduction of microglia, they have more plaque-associated microglia than B6.APP/PS1 (Onos et al., 2019) and display a proliferative (Ki67+) phenotype. This phenotype is reminiscent of that observed in 5XFAD mice, however, in these animals the microglia are protective (Wang et al., 2016). Therefore, it will be quite interesting to dig more into these wild-derived strains, their pathology, and the impact of various pathways in disease progression.

    This report may help reconcile the discrepancy between microglia scRNA-Seq profiles seen in mouse amyloid models and those found in human Alzheimer’s disease (AD) samples (Keren-Shaul et al., 2017; Mathys et al., 2019; Zhou et al., 2020). Indeed, the scRNA-Seq profile in wild-derived mice aligned well with the human snRNA-Seq dataset from Li-Huei Tsai’s group (Mathys et al., 2019). However, this alignment relies on many ribosomal proteins and not on classical DAM genes (Mathys et al., 2019). The enrichment of ribosomal genes within certain mouse and human clusters may increase homogeneity, enhancing statistical significance of the similarities. Moreover, some microglial genes found by our group in human AD, such as IRF8 and CHI3L1 (Zhou et al., 2020), are not found in APP/PS1 mice. Thus, the discrepancy between mouse models and human AD will require further investigations.

    One of the potential explanations for mouse-human differences is that the amyloid mouse models fail to recapitulate much of the AD pathology, including brain atrophy and tauopathy. And since different types of tissue damage may elicit different microglial genes, the mouse microglial signatures may track with the human ones. This problem also complicates attempts to bridge mouse and human transcriptome and proteomics results.

    The strains reported here by the Howell lab might be a powerful tool to mimic the genetic diversity of human cohorts, especially if all wild-derived strains are analyzed together as a large cohort. The study also opens other interesting possibilities worth mentioning. For example, wild-derived strains can be examined for microglia communications with other CNS cells. In our previous work, we have shown that astrocytes, oligodendrocytes, and neurons adopt AD-associated transcriptional signatures, which may contribute to the response to AD pathology, such as expression of Serpina3n and C4b (Zhou et al., 2020). Whether similar changes are present in wild-derived mice as well as AD patients remains uninvestigated.

    Further, while here the authors profiled female wild-derived strains at 9 months of age, their previous publications indicated sex differences in amyloid pathology in both CAST and WSB backgrounds. Thus, it will be interesting to investigate whether sex differences differentially contribute to amyloid pathology among these wild-derived strains compared with the B6 lab strain.

    References:

    . Enhancing face validity of mouse models of Alzheimer's disease with natural genetic variation. PLoS Genet. 2019 May;15(5):e1008155. Epub 2019 May 31 PubMed.

    . TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med. 2016 May 2;213(5):667-75. Epub 2016 Apr 18 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.

    . Author Correction: Single-cell transcriptomic analysis of Alzheimer's disease. Nature. 2019 Jul;571(7763):E1. PubMed.

    . Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease. Nat Med. 2020 Jan;26(1):131-142. Epub 2020 Jan 13 PubMed.

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