Zhou Y, Tada M, Cai Z, Andhey PS, Swain A, Miller KR, Gilfillan S, Artyomov MN, Takao M, Kakita A, Colonna M. Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia. Nat Immunol. 2023 Mar;24(3):545-557. Epub 2023 Jan 19 PubMed. Correction.

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  1. TREM2 and DAP12/TYROBP are microglial proteins that form a complex involved in sensing extracellular debris in the interstitial spaces of the brain. Mutations in both genes are linked to neurodegenerative disorders. Missense mutations in both genes are associated with Alzheimer’s disease (AD), while loss-of-function and deletion mutants are associated with Nasu-Hakola disease (NHD). Here, Zhou et al. describe the transcriptomic profile of human brains from NHD patients who harbored homozygous loss-of-function mutations in DAP12. The microglia in the human NHD brains showed a unique signature of injury-response genes, particularly those in pathways including RUNX1, STAT3, and TGFb. This signature overlapped with others that have been associated with interleukin 10 stimulation, and NicheNet analysis implicated FGF2 as the ligand most likely to be responsible.

    Next, Zhou et al. turned to brains from mice expressing a mutant form of DAP12/TYROBP, known as KDY75. This mouse was created by with the intention of impairing DAP12/TYROBP dimerization and signaling, a goal that succeeded through an unusual strategy in which a polypeptide that does not exist in nature, G75-I90, was substituted for the wild-type dimerization domain Y75-R86 (Tomasello et al., 2000). The spliced-in G75-I90 domain retains one of the two phosphorylatable tyrosine residues present in the wild-type Y75-R86 domain. The inclusion of a nonphysiological, potentially phosphorylatable domain raises the question of how to interpret RNA sequencing data derived from KDY75 mice, particularly relative to more conventional knockout mice. KDY75 mice were impaired in their ability to develop the age-associated microglial (AM) signature that has now become associated with the response to Aβ. The authors conclude that the AM/Aβ response phenotype requires DAP12/TYROBP signaling.

    Our laboratory has been investigating the role of DAP12/TYROBP in microglial signaling in mouse models of AD. Our experience using a conventional, constitutive DAP12/TYROBP knockout, deleting exons 3 and 4, is consistent with Zhou et al.’s report using KDY75 mice: i.e., in the absence of an immune stimulus or pathology, the transcriptomic effects of both knockout strategies are modest (Haure-Mirande et al., 2017, 2019, 2022). We observed that the AM/Aβ response phenotype was reduced when we crossed conventional DAP12/TYROBP knockouts with PSAPP mice. Unexpectedly, however, the DAP12/TYROBP deficiency sustained normal learning/memory and electrophysiology in the face of the identical amyloid burden of PSAPP mice.

    In unpublished work, we have performed single-cell sequencing on the hippocampus from the Tyrobp -/- D exons 3,4 conventional knockout mice (age 20 months). With a focus on microglia, the divergence between top microglial differentially expressed genes (DEGs) ranked by adjusted p value is an obvious metric, demonstrating key differences between the two lines, and few of the top-ranked DEGs in the KD75 model are even significant in the Tyrobp -/- D exons 3/4 line (e.g., fewer than 10 percent are shared at p<0.05 and fewer than 30 percent are shared at p<0.1). In our opinion, the limited overlap between the microglial DEGs from the KDY75 mice and those of the conventional DAP12 knockout argues that the KDY75 DAP12 mouse is not equivalent to a conventional DAP12 knockout. There are also major differences between the two mice in transcriptomic changes in other cell types. However, while it is unclear whether these differences are functionally important, there is a very important similarity in that neither model recapitulates NHD.

    References:

    Haure-Mirande JV, Audrain M, Fanutza T, Kim SH, Klein WL, Glabe C, Readhead B, Dudley JT, Blitzer RD, Wang M, Zhang B, Schadt EE, Gandy S, Ehrlich ME. Deficiency of TYROBP, an adapter protein for TREM2 and CR3 receptors, is neuroprotective in a mouse model of early Alzheimer's pathology. Acta Neuropathol. 2017 Nov;134(5):769-788. Epub 2017 Jun 13 PubMed.

    Haure-Mirande JV, Wang M, Audrain M, Fanutza T, Kim SH, Heja S, Readhead B, Dudley JT, Blitzer RD, Schadt EE, Zhang B, Gandy S, Ehrlich ME. Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in cerebral Aβ amyloidosis mouse normalizes clinical phenotype and complement subnetwork molecular pathology without reducing Aβ burden. Mol Psychiatry. 2019 Mar;24(3):431-446. Epub 2018 Oct 3 PubMed.

    Haure-Mirande JV, Audrain M, Ehrlich ME, Gandy S. Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2. Mol Neurodegener. 2022 Aug 24;17(1):55. PubMed.

    Tomasello E, Desmoulins PO, Chemin K, Guia S, Cremer H, Ortaldo J, Love P, Kaiserlian D, Vivier E. Combined natural killer cell and dendritic cell functional deficiency in KARAP/DAP12 loss-of-function mutant mice. Immunity. 2000 Sep;13(3):355-64. PubMed.

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  1. In Nasu-Hakola Disease, DAP12-Deficient Microglia Kick Repair into Overdrive