Reduced TREM2 activation in microglia of patients with Alzheimer's disease

Okuzono, Yuumi; Sakuma, Hiroyuki; Miyakawa, Shuuichi; Ifuku, Masataka; Lee, Jong-Hun; Das, Debarati; Banerjee, Saumyabrata; Zhao, Yang; Yamamoto, Kōji; Ando, Tatsuya; Satoh, Shuji

doi:10.1002/2211-5463.13300

Cited by 17 publications

(23 citation statements)

References 99 publications

(151 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Triggering receptor expressed on myeloid cells 2 (Trem2) is a single pass transmembrane receptor that activates a range of signaling pathways associated with immune function through ligand binding ( 51 ). Trem2 has been used as a microglial activation marker and a general requirement for its activation ( 29 , 52 ). Galectin-3 can bind to the Trem2, activate microglia, and induce neuroinflammatory responses in an AD mouse model, our recent study confirmed that inhibition of endogenous Trem2 ligand ameliorates DCD by inhibiting oxidative stress and neuroinflammation ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction

Liu

et al. 2022

Front. Endocrinol.

View full text Add to dashboard Cite

Diabetes-associated cognitive decline (DCD), is one of the complications of diabetes, which is characterized by a series of neurophysiological and pathological abnormalities. However, the exact pathogenesis of DCD is still unknown. Single-cell RNA sequencing (scRNA-seq) could discover unusual subpopulations, explore functional heterogeneity and identify signaling pathways and potential markers. The aim of this research was to provide deeper opinion into molecular and cellular changes underlying DCD, identify different cellular types of the diabetic mice hippocampus at single-cell level, and elucidate the factors mediating the pathogenesis of DCD. To elucidate cell specific gene expression changes in the hippocampus of diabetic encephalopathy. Single-cell RNA sequencing of hippocampus from db/m and db/db mice was carried out. Subclustering analysis was performed to further describe microglial cell subpopulations. Interestingly using immunohistochemistry, these findings were confirmed at the protein level. Single cell analysis yielded transcriptome data for 14621 hippocampal cells and defined 11 different cell types. Analysis of differentially expressed genes in the microglia compartments indicated that infection- and immune system process- associated terms, oxidative stress and inflammation play vital roles in the progression of DCD. Compared with db/m mouse, experiments at the protein level supported the activation of microglia, increased expression of inflammatory factors and oxidative stress damage in the hippocampus of db/db mouse. In addition, a major finding of our research was the subpopulation of microglia that express genes related to pro-inflammatory disease-associated microglia (DAM). Our research reveals pathological alterations of inflammation and oxidative stress mediated hippocampal damage in the db/db mice, and may provide potential diagnostic biomarkers and therapeutic interventions for DCD.

show abstract

Section: Discussionmentioning

confidence: 99%

Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction

Liu

et al. 2022

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…In addition, APOE can act as a ligand for TREM2 and the TREM2-APOE pathway acts as a regulator that can help restore homeostatic microglia (Krasemann et al, 2017). Okuzono et al (2021) found that activation of TREM2 in AD may lead to anti-apoptotic signaling, immune responses and cytoskeletal alterations in microglia. On the contrary, CD33 inhibits anti-inflammatory signal transduction, cell adhesion and endocytosis of microglia, increasing the risk of AD (Ryan et al, 2017).…”

Section: Microglia-associated Immune Receptors and Alzheimer's Diseasementioning

confidence: 99%

The Role of Microglia in Alzheimer’s Disease From the Perspective of Immune Inflammation and Iron Metabolism

Long

Zhou

Cheng

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD), the most common type of senile dementia, includes the complex pathogenesis of abnormal deposition of amyloid beta-protein (Aβ), phosphorylated tau (p-tau) and neuroimmune inflammatory. The neurodegenerative process of AD triggers microglial activation, and the overactivation of microglia produces a large number of neuroimmune inflammatory factors. Microglia dysfunction can lead to disturbances in iron metabolism and enhance iron-induced neuronal degeneration in AD, while elevated iron levels in brain areas affect microglia phenotype and function. In this manuscript, we firstly discuss the role of microglia in AD and then introduce the role of microglia in the immune-inflammatory pathology of AD. Their role in AD iron homeostasis is emphasized. Recent studies on microglia and ferroptosis in AD are also reviewed. It will help readers better understand the role of microglia in iron metabolism in AD, and provides a basis for better regulation of iron metabolism disorders in AD and the discovery of new potential therapeutic targets for AD.

show abstract

“… 199 , 200 Moreover, it has been observed that TREM2 activation decreases with AD progression. 198 TREM2 activation was lower in AD microglia than in microglia from healthy subjects or patients with mild cognitive impairment. 198 TREM2 activation in AD may lead to anti-apoptotic signaling, immune response, and cytoskeletal changes in the microglia, supporting a protective role of TREM2 activation in AD.…”

Section: Potential Strategies To Combat Ad Based On Modifying the Act...mentioning

confidence: 81%

“… 198 TREM2 activation in AD may lead to anti-apoptotic signaling, immune response, and cytoskeletal changes in the microglia, supporting a protective role of TREM2 activation in AD. 198 Anti-TREM2-specific agonistic antibodies, such Hyb87, 4D9, 201 AL002 202 (the most advanced from Alector now in phase II clinical trial Supplemental Data 6 ) may become the most effective therapeutic agents against AD.…”

Section: Potential Strategies To Combat Ad Based On Modifying the Act...mentioning

confidence: 83%

“… 140 , 192 Using an anti-TREM2-specific agonistic antibody, Hyb87, has been identified 300 upregulated and 251 downregulated expressions of microglial genes. 198 In cells activated via TREM2, phagocytosis and lipid metabolism are increased. TREM2 variants (or in the signaling adapter DAP12) as well as loss-of-function of this receptor, have been linked to different types of neurodegenerative disorders such as AD.…”

Section: Potential Strategies To Combat Ad Based On Modifying the Act...mentioning

confidence: 99%

See 1 more Smart Citation

The relationships between neuroglial and neuronal changes in Alzheimer’s disease, and the related controversies II: gliotherapies and multimodal therapy

Toledano-Dı́az¹,

Álvarez

Toledano

2022

J Cent Nerv Syst Dis

View full text Add to dashboard Cite

Since the original description of Alzheimer´s disease (AD), research into this condition has mainly focused on assessing the alterations to neurons associated with dementia, and those to the circuits in which they are involved. In most of the studies on human brains and in many models of AD, the glial cells accompanying these neurons undergo concomitant alterations that aggravate the course of neurodegeneration. As a result, these changes to neuroglial cells are now included in all the “pathogenic cascades” described in AD. Accordingly, astrogliosis and microgliosis, the main components of neuroinflammation, have been integrated into all the pathogenic theories of this disease, as discussed in this part of the two-part monograph that follows an accompanying article on gliopathogenesis and glioprotection. This initial reflection verified the implication of alterations to the neuroglia in AD, suggesting that these cells may also represent therapeutic targets to prevent neurodegeneration. In this second part of the monograph, we will analyze the possibilities of acting on glial cells to prevent or treat the neurodegeneration that is the hallmark of AD and other pathologies. Evidence of the potential of different pharmacological, non-pharmacological, cell and gene therapies (widely treated) to prevent or treat this disease is now forthcoming, in most cases as adjuncts to other therapies. A comprehensive AD multimodal therapy is proposed in which neuronal and neuroglial pharmacological treatments are jointly considered, as well as the use of new cell and gene therapies and non-pharmacological therapies that tend to slow down the progress of dementia.

show abstract

Reduced TREM2 activation in microglia of patients with Alzheimer's disease

Cited by 17 publications

References 99 publications

Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction

Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction

The Role of Microglia in Alzheimer’s Disease From the Perspective of Immune Inflammation and Iron Metabolism

The relationships between neuroglial and neuronal changes in Alzheimer’s disease, and the related controversies II: gliotherapies and multimodal therapy

Contact Info

Product

Resources

About