Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's ' s Disease and Multiple Sclerosis

被引：14

作者：

Etxeberria, Ainhoa ^{[1
]}

Shen, Yun-An A. ^{[1
]}

Vito, Stephen ^{[1
]}

Silverman, Sean M. ^{[1
]}

Imperio, Jose ^{[1
]}

Lalehzadeh, Guita ^{[1
]}

Soung, Allison L. ^{[1
]}

Du, Changchun

Xie, Luke ^{[3
]}

Choy, Man Kin ^{[3
]}

Hsiao, Yi-chun ^{[4
]}

Ngu, Hai ^{[5
]}

Cho, Chang Hoon ^{[2
,6
]}

Ghosh, Soumitra ^{[1
]}

Novikova, Gloriia ^{[7
]}

Rezzonico, Mitchell G. ^{[7
]}

Leahey, Rebecca ^{[1
]}

Weber, Martin ^{[1
]}

Gogineni, Alvin ^{[3
]}

Elstrott, Justin ^{[3
]}

Xiong, Monica ^{[1
]}

Greene, Jacob J. ^{[1
]}

Stark, Kimberly L. ^{[1
]}

Chan, Pamela ^{[1
,2
]}

Roth, Gillie A. ^{[8
]}

Adrian, Max ^{[5
]}

Li, Qingling ^{[9
]}

Choi, Meena ^{[9
]}

Wong, Weng Ruh ^{[9
]}

Sandoval, Wendy ^{[9
]}

Foreman, Oded ^{[5
]}

Nugent, Alicia A. ^{[6
]}

Friedman, Brad A. ^{[7
]}

Sadekar, Shraddha ^{[8
]}

Hotzel, Isidro ^{[4
]}

V. Hansen, David ^{[1
]}

Chih, Ben ^{[1
,2
]}

Yuen, Tracy J. ^{[1
]}

Weimer, Robby M. ^{[3
]}

Easton, Amy ^{[1
]}

Meilandt, William J. ^{[1
]}

Bohlen, Christopher J. ^{[1
]}

机构：

[1] Genentech Inc, Dept Neurosci, South San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Biochem & Cellular Pharmacol, South San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Translat Imaging, South San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Antibody Engn, South San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Pathol, South San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Human Pathobiol & OMNI Reverse Translat, South San Francisco, CA 94080 USA

[7] Genentech Inc, Dept Bioinformat, South San Francisco, CA 94080 USA

[8] Genentech Inc, Dept Preclin & Translat Pharmacokinet & Pharmacody, South San Francisco, CA 94080 USA

[9] Genentech Inc, Dept Microchem Lipid & Prote, South San Francisco, CA 94080 USA

来源：

JOURNAL OF NEUROSCIENCE | 2024年 / 44卷 / 29期

关键词：

Alzheimer's disease; antibody; microglia; multiple sclerosis; myelin repair; TREM2; MICROGLIAL RESPONSES; TRANSGENIC MICE; A-BETA; RECEPTOR; EXPRESSION; TAU; IMPAIRS; NEUROINFLAMMATION; NEURODEGENERATION; ACTIVATION;

D O I：

10.1523/JNEUROSCI.2347-23.2024

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Human genetics and preclinical studies have identified fi ed key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's ' s disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-beta beta (A beta) beta ) pathology (PS2APP) or combined A beta beta and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.

引用

页数：30

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