TLQP-21 mediated activation of microglial BV2 cells promotes clearance of extracellular fibril amyloid-β

Cho, Kwangmin; Jang, Youjin; Lee, Se-Jong; Jeon, Yu-Na; Shim, Young-Lim; Lee, Ji Yong; Lim, Da-Som; Kim, Dong-Hou; Yoon, Seung-Yong

doi:10.1016/j.bbrc.2020.01.111

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…Indeed, the data presented here are consistent with causal roles for TLQP-62 and the VGF proprotein in AD pathogenesis and progression, but do not rule out contributions of other VGF-derived peptides including TLQP-21, an activator of the C3aR1 complement receptor 66 . Of note, we and others have recently shown that TLQP-21 reduces neuropathology in male 5xFAD mice and increases amyloid uptake in transformed BV2 mouse microglia and in primary cultured mouse microglia via a C3aR1-dependent pathway [87][88][89] , consistent with the previous identification of a critical complement network module in AD 5 .…”

Section: Discussionsupporting

confidence: 91%

Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease

et al. 2020

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Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene-and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.

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Section: Discussionsupporting

confidence: 91%

Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease

et al. 2020

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“…Another cellular model that has been often used to probe TLQP-21 activity is microglia [29][30][31]. TLQP-21 increases the phagocytic potential of microglia via the uptake of fibrillar amyloid-β (fAβ) or fluorescently labeled beads, as well as by increasing cell migration in a wound healing assay [29].…”

Section: Tissue Distribution and Regulation Of Expressionmentioning

confidence: 99%

“…The predominant cell type in which C3aR1 is expressed are macrophages and other immune cells, while expression in other stromal cells and adipocytes has also been reported [4,28,46,[49][50][51]. Regarding expression in the CNS, multiple studies have shown robust C3aR1 expression in microglia [7,[29][30][31]52]. The C3aR1 molecular pharmacology is incompletely understood.…”

Section: Identification Of C3ar1 As the Tlqp-21 Receptormentioning

confidence: 99%

“…TLQP-21 activates microglia to induce calcium mobilization [ 7 ], uptake of fibrillary amyloid-β [ 29 ] and, finally to regulate inflammatory pain [ 7 ]. Two independent studies demonstrate that knocking down (KD) C3aR1 using siRNA in the BV2 microglial cell line [ 31 ] or microglia from C3aR1-deficient mice [ 29 ], result in decreased basal phagocytosis, prevents TLQP-21 induced uptake of fibrillary amyloid-β and prevents TLQP-21 evoked calcium mobilization. It was also observed that the differentially expressed genes upon TLQP-21 administration were abrogated by C3aR1 deletion in primary microglia [ 29 ].…”

Section: The Identity Of the Tlqp-21 Receptormentioning

confidence: 99%

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The molecular identity of the TLQP-21 peptide receptor

Sahu

Nguyen

Rodrı́guez

et al. 2021

Cell. Mol. Life Sci.

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The TLQP-21 neuropeptide has been implicated in functions as diverse as lipolysis, neurodegeneration and metabolism, thus suggesting an important role in several human diseases. Three binding targets have been proposed for TLQP-21: C3aR1, gC1qR and HSPA8. The aim of this review is to critically evaluate the molecular identity of the TLQP-21 receptor and the proposed multi-receptor mechanism of action. Several studies confirm a critical role for C3aR1 in TLQP-21 biological activity and a largely conserved mode of binding, receptor activation and signaling with C3a, its first-identified endogenous ligand. Conversely, data supporting a role of gC1qR and HSPA8 in TLQP-21 activity remain limited, with no signal transduction pathways being described. Overall, C3aR1 is the only receptor for which a necessary and sufficient role in TLQP-21 activity has been confirmed thus far. This conclusion calls into question the validity of a multi-receptor mechanism of action for TLQP-21 and should inform future studies.

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“…Neurosecretory protein VGF is a nerve growth factor that regulates neuronal development and activity through processing of the precursor protein into bioactive peptides. One such peptide, TLQP-21, has been shown to enhance Aβ clearance through microglial phagocytosis and to promote fibrillar Aβ uptake by microglial BV2 cells through a complement C3a receptor-1 (C3aR1)-dependent mechanism [ 257 ]. A more recent study further demonstrated TLQP-21 mediated microglial modulation via C3aR1 using wild-type and C3aR1-null mouse models [ 258 ].…”

Section: Survey Of Extracellular Proteins That Associate With Aβmentioning

confidence: 99%

Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

Rahman

Lendel

2021

Mol Neurodegeneration

115

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Alzheimer’s disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments in intracellular neurofibrillary tangles. Extensive research has focused on understanding the assembly mechanisms and neurotoxic effects of Aβ during the last decades but still we only have a brief understanding of the disease associated biological processes. This review highlights the many other constituents that, beside Aβ, are accumulated in the plaques, with the focus on extracellular proteins. All living organisms rely on a delicate network of protein functionality. Deposition of significant amounts of certain proteins in insoluble inclusions will unquestionably lead to disturbances in the network, which may contribute to AD and copathology. This paper provide a comprehensive overview of extracellular proteins that have been shown to interact with Aβ and a discussion of their potential roles in AD pathology. Methods that can expand the knowledge about how the proteins are incorporated in plaques are described. Top-down methods to analyze post-mortem tissue and bottom-up approaches with the potential to provide molecular insights on the organization of plaque-like particles are compared. Finally, a network analysis of Aβ-interacting partners with enriched functional and structural key words is presented.

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TLQP-21 mediated activation of microglial BV2 cells promotes clearance of extracellular fibril amyloid-β

Cited by 14 publications

References 41 publications

Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease

Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease

The molecular identity of the TLQP-21 peptide receptor

Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology

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