Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition

Price, Brittani R.; Sudduth, Tiffany L.; Weekman, Erica M.; Johnson, Sherika N.; Hawthorne, Danielle; Woolums, Abigail; Wilcock, Donna M.

doi:10.1186/s12974-020-01915-0

Cited by 73 publications

(74 citation statements)

References 68 publications

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“…Single-cell RNA sequencing analysis has revealed that TREM2 is critical for the second step of DAM activation (Keren-Shaul et al, 2017). Overexpression of TREM2 reduced the level of pro-inflammatory cytokines in microglia, whereas TREM2-activating antibody induced significant increases in both pro-inflammatory [IL-1β, TNF-α, C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)10, Gata3, Rorc] and anti-inflammatory (YM1 and IL1Rn) marker expression in 5 × FAD mice (Long et al, 2019;Price et al, 2020). Thus, TREM2 has complex functions in AD.…”

Section: Triggering Receptor Expressed On Myeloid Cells 2 and Toll-limentioning

confidence: 99%

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment

Zhou

Chen

et al. 2020

Front. Neurosci.

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Alzheimer disease (AD) is a devastating neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta and formation of intracellular neurofibrillary tangles. Microglia activation and neuroinflammation play important roles in the pathogenesis of AD; Toll-like receptor 4 (TLR4)—a key component of the innate immune system—in microglia is also thought to be involved based on the observed association between TLR gene polymorphisms and AD risk. TLR4 has been shown to exert both detrimental and beneficial effects on AD-related pathologies. In preclinical models, experimental manipulations targeting TLR4 were shown to improve learning and memory, which was related to inhibition of pro-inflammatory cytokine release and reduction of oxidative stress. In this review, we summarize the key evidence supporting TLR4 as a promising therapeutic target in AD treatment.

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Section: Triggering Receptor Expressed On Myeloid Cells 2 and Toll-limentioning

confidence: 99%

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment

Zhou

Chen

et al. 2020

Front. Neurosci.

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“…Recently, agonistic activity of anti‐TREM2 antibodies have been described (Price et al, 2020; Schlepckow et al, 2020; S. Wang et al, 2020). We developed a mouse monoclonal antibody against human TREM2 using the complete ectodomain of human TREM2 for immunization.…”

Section: Resultsmentioning

confidence: 99%

“…Since the disease‐associated variants studied here cause a partial or almost complete loss‐of‐function, activation of TREM2‐DAP12 signaling could potentially represent a therapeutic approach to normalize regulation of microglial activity (Wes, Sayed, Bard, & Gan, 2016). Indeed, agonistic antibodies have been used to activate TREM2 signaling and even restore some cellular deficits observed in TREM2 R47H expressing cells (Cheng et al, 2018; Price et al, 2020; Schlepckow et al, 2020; S. Wang et al, 2020). The monoclonal anti TREM2 antibody 4B2A3 described here also had agonistic effects on TREM2‐DAP12 signaling.…”

Section: Discussionmentioning

confidence: 99%

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A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease‐associated variants on receptor signaling and activation by antibodies against the stalk region

Ibach

Mathews

Linnartz‐Gerlach

et al. 2020

Glia

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The triggering receptor expressed on myeloid cells 2 (TREM2) is an immune receptor expressed on myeloid‐derived cell types. The extracellular immunoglobulin‐like domain of TREM2 binds anionic ligands including Apolipoprotein E and Amyloid‐β. The transmembrane domain interacts with its adaptor protein DAP12/TYROBP that is responsible for propagation of downstream signaling upon ligand interaction. Several sequence variants of TREM2 have been linked to different neurodegenerative diseases including Alzheimer's disease. Here, we generated HEK 293 Flp‐In cell lines stably expressing human TREM2 and DAP12 using a bicistronic construct with a T2A linker sequence allowing initial expression of both proteins in stoichiometric amounts. Cell biological and biochemical analyses revealed transport of TREM2 to the cell surface, and canonical sequential proteolytic processing and shedding of TREM2 (sTREM2). The functionality of this cell system was demonstrated by detection of phosphorylated spleen tyrosine kinase (SYK) upon stimulation of TREM2 with the anionic membrane lipid phosphatidylserine or anti‐TREM2 antibodies. Using this cell model, we demonstrated impaired signaling of disease associated TREM2 variants. We also identified a monoclonal antibody against the stalk region of TREM2 with agonistic activity. Activation of TREM2‐DAP12 signaling with the monoclonal antibody and the partial loss of function of disease associated variants were recapitulated in induced pluripotent stem cell derived microglia. Thus, this reporter cell model represents a suitable experimental system to investigate signaling of TREM2 variants, and for the identification of ligands and compounds that modulate TREM2‐DAP12 signaling. MAIN POINTS Disease associated variants impair the signaling activity of TREM2 by distinct mechanisms. Targeting the stalk region of TREM2 with bivalent antibodies activates TREM2 signaling.

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APOE and immunity: Research highlights

Kloske

Barnum²,

Batista

et al. 2023

Alzheimer's & Dementia

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INTRODUCTION:At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS:The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS:During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor α [TNFα]).DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development.

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Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition

Cited by 73 publications

References 68 publications

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment

TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment

A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease‐associated variants on receptor signaling and activation by antibodies against the stalk region

APOE and immunity: Research highlights

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