Audrain M, Haure-Mirande JV, Mleczko J, Wang M, Griffin JK, St George-Hyslop PH, Fraser P, Zhang B, Gandy S, Ehrlich ME. Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice. Alzheimers Dement. 2021 Feb;17(2):149-163. Epub 2020 Dec 12 PubMed.
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Icahn School of Medicine
Icahn School of Medicine at Mount Sinai
We appreciate Helen Santoro’s thorough summary. We are writing to clarify comments attributed to Christian Haass that may not have considered the totality of key data upon which we base our conclusions:
(1) In paragraph 10, Haass is quoted as saying “…nor did they prove their hypothesis by investigating TYROBP/ApoE single- and double-KO mice…” On the contrary, the molecular characterization of microglial phenotypes from TYROBP KO mice forms the underpinning for our conclusion that there exists a TYROBP-dependent pathway that can mediate the transformation of homeostatic microglia to disease-associated microglia (DAM) in the absence of TREM2.
(2) In paragraph 12, “… Haass stressed that TREM2 is still present in the mice with overexpressed TYROBP…” Our evidence for the existence of a TREM2-independent pathway in microglia is derived from studies of TREM2 knockout mice, not from data using TYROBP-overexpressing (Iba1Tyrobp) mice. Endogenous TREM2 is present in TYROBP-overexpressing (Iba1Tyrobp) mice, and their phenotype is what led us to further investigate the TYROBP and TREM2 KO mice.
We are in complete agreement that “the DAM pathway is too complicated to be governed solely by TREM2 or TYROBP.”
The intent of our paper is to highlight the possible existence of roles for microglial TYROBP that are demonstrable even in the brains of TREM2 knockout mice.
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