Microglia respond to Alzheimer's disease (AD) with varied transcriptional responses. We show that oligomeric Aß (oAß) induces the expression of Hif1a and Egln3 in microglia in vitro, together with the transcription of the type I interferon signature (IFNS) genes in a PHD3-dependent manner. We identify FOXO3 as a repressor of IFNS, whose abundance decreases upon PHD3 induction in response to oAß. In vivo, loss of PHD3 correlates with abrogation of the IFNS and activation of the disease-associated microglia signature, an increase in microglia proximity to Aß plaques and phagocytosis of both Aß and small plaques. PHD3 deficiency mitigated the Aß plaque-associated neuropathology and rescued behavioral deficits of an AD mouse model. Last, we demonstrate that microglial PHD3 overexpression in the absence of Aß pathology is sufficient to induce the IFNS and behavioral alterations. Together, our data strongly indicate that the inactivation of the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, improving AD outcome.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by amyloid-beta (Aβ) accumulation and neuroinflammation. A previous multicenter, phase 2, double-blind, placebo-controlled trial randomized 179 participants into placebo or resveratrol over 52 weeks. Sub-analysis of CSF biomarkers of neuronal damage, inflammation, and microglial activity was performed in a subset of patients treated with a placebo (n = 21) versus resveratrol (n = 30). Markers of neuronal damage, including neuron-specific enolase and hyperphosphorylated neurofilaments, were reduced. Microglial activation was measured via a triggering receptor expressed on myeloid cells (TREM)-2 at baseline and after resveratrol treatment. Resveratrol significantly reduced CSF TREM2 levels and decreased inflammation and tissue damage, including matrix metalloprotease (MMP)-9. Cathepsin D, a lysosomal marker of autophagy, was reduced in the resveratrol group compared with placebo, while angiogenin, a marker of vascular angiogenesis, was increased. These data suggest that resveratrol may exert anti-inflammatory and neuroprotective effects in AD by reducing CSF TREM2 and other markers of neuronal damage. Further research is needed to assess the significance of these biomarker changes on clinical outcomes in patients with neurodegenerative diseases.

Cognitive impairment in Parkinson's disease (PD) is a widespread and rapidly progressive feature that impacts prognosis. Although TREM2 has been implicated in neuroprotection across various neurodegenerative diseases, its specific role in PD remains to be clarified. In this study, we first detected the hippocampus of human PD specimens and of the mutant A53T α-Synuclein transgenic mice (A53T mice), and found a significant increase in the number of TREM2+ microglia. To evaluate the effects of TREM2 deficiency, TREM2-deficient A53T mice (TREM2-/-/A53T mice) were generated. In these mice, exacerbated cognitive impairment, neurodegeneration, disruption of synaptic plasticity, and accumulation of pathological α-Synuclein (α-Syn) in the hippocampus were observed, without any detected motor dysfunction. Despite increased infiltration of activated microglia surrounding α-Syn aggregates, lysosomal dysfunction in microglia was aggravated in the TREM2-/-/A53T mice. In addition, transcriptional analyses and in vitro experiments further found that TREM2 knockdown inhibited the nuclear distribution of TFEB via the ERK1/2 pathway, exacerbating α-Syn-induced lysosomal dysfunction and causing more pathological α-Syn accumulation. Finally, HT22 cells were cocultured with TREM2 knockdown of BV-2 cells pretreated with recombinant human A53T α-Syn preformed fibrils (PFFs). The coculture experiments showed that TREM2 knockdown in BV-2 cells pretreated with PFFs enhanced the phosphorylation of α-Syn and promoted apoptosis in HT22 cells via inhibiting α-Syn degradation. In conclusion, TREM2 deficiency exacerbates cognitive impairment in PD by exacerbating α-Syn-induced microglial lysosomal dysfunction, identifying TREM2 as a potential therapeutic target.

Cardiovascular diseases (CVDs) are the leading cause of global mortality, with immune responses playing a central role in their pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) is a key immune regulator in CVDs, influencing inflammation, lipid metabolism, and tissue repair. This review comprehensively examines TREM2's structure, function, and signaling pathways, highlighting its roles in atherosclerosis, myocardial infarction, hypertension, atrial fibrillation, and heart failure. In atherosclerosis, macrophages with high TREM2 expression (TREM2hi macrophages) promote plaque progression in early stages but enhance plaque stability in advanced stages. In myocardial infarction, TREM2 modulates macrophage diversity and efferocytosis, aiding cardiac repair. TREM2 also plays a protective role in hypertensive heart disease by reducing inflammation and promoting tissue repair. Challenges in targeting TREM2 therapeutically include its context-dependent effects and complex signaling pathways. Future research should focus on elucidating TREM2's mechanisms in CVDs and developing stage-specific therapies.

Dementia represents a growing public health challenge, affecting an increasing number of individuals. It encompasses a broad spectrum of cognitive impairments, ranging from mild to severe stages, each of which demands varying levels of care. Current diagnostic approaches often treat dementia as a uniform condition, potentially overlooking clinically significant subtypes, which limits the effectiveness of treatment and care strategies. This study seeks to address the limitations of traditional diagnostic methods by applying unsupervised machine learning techniques to a large, multi-modal dataset of dementia patients (encompassing multiple data sources including clinical, demographic, gene expression and protein concentrations), with the aim of identifying distinct subtypes within the population. The primary focus is on differentiating between mild and severe stages of dementia to improve diagnostic accuracy and personalize treatment plans.

The dataset analyzed included 911 individuals, described by 157 multi-modal characteristics, encompassing clinical, genomic, proteomic and sociodemographic features. After handling missing data, the dataset was reduced to 561 rows and 135 columns. Various dimensionality reduction techniques were applied to improve the feature-to-patient ratio, and unsupervised clustering methods were employed to identify potential subtypes. The major novelty in our methodology regards the combination of different techniques, bridging high-dimensional statistical inference, multi-modal dimensionality reduction and clustering analysis, to appropriately model the multi-modal nature of the data and ensure clinical relevance.

The analysis revealed distinct clusters within the dementia population, each characterized by specific clinical and demographic profiles. These profiles included variations in biomarkers, cognitive scores, and disability levels. The findings suggest the presence of previously unrecognized subgroups, distinguished by their genomic, proteomic, and clinical characteristics.

This study demonstrates that unsupervised machine learning can effectively identify clinically relevant subtypes of dementia, with important implications for diagnosis and personalized treatment. Further research is required to validate these findings and investigate their potential to improve patient outcomes.

Disease-Associated Microglia (DAM) are a focus in Alzheimer's disease (AD) research due to their central involvement in the response to amyloid-beta plaques. Microglial Toll-like receptor 4 (TLR4) is instrumental in the binding of fibrillary amyloid proteins, while Lyn kinase (Lyn) is a member of the Src family of non-receptor tyrosine kinases involved in immune signaling. Lyn is a novel, non-canonical, intracellular adaptor with diverse roles in cell-specific signaling which directly binds to TLR4 to modify its function. Lyn can be activated in response to TLR4 stimulation, leading to phosphorylation of various substrates and modulation of inflammatory and phagocytosis signaling pathways. Here, we investigated the TLR4-Lyn interaction in neuroinflammation using WT, 5XFAD, and 5XFAD x Lyn-/- mouse models by western blotting (WB), co-immunoprecipitation (co-IP), immunohistochemistry (IHC) and flow cytometric (FC) analysis. A spatial transcriptomic analysis of microglia in WT, 5XFAD, and 5XFAD x Lyn-/- mice revealed essential genes involved in neuroinflammation, Aβ phagocytosis, and neuronal damage. Finally, we explored the effects of a synthetic, TLR4-Lyn modulator protein (TLIM) through an in vitro AD model using primary murine microglia. Our WB, co-IP, IHC, and FC data show an increased, novel, direct protein-protein interaction between TLR4 and Lyn kinase in the brains of 5XFAD mice compared to WT. Furthermore, in the absence of Lyn (5XFAD x Lyn-/- mice); increased expression of protective Syk kinase was observed, enhanced microglial Aβ phagocytosis, increased astrocyte activity, decreased neuronal dystrophy, and a further increase in the cell survival signaling and protective DAM population was noted. The DAM population in 5XFAD mice which produce more inflammatory cytokines and phagocytose more Aβ were observed to express greater levels of TLR4 and Lyn. Pathway analysis comparison between WT, 5XFAD, and 5XFAD x Lyn-/- mice supported these findings via our microglial spatial transcriptomic analysis. Finally, we created an in vitro co-culture system with primary murine microglial and primary murine hippocampal cells exposed to Aβ as a model of AD. When these co-cultures were treated with our TLR4-Lyn Interaction Modulators (TLIMs), an increase in Aβ phagocytosis and a decrease in neuronal dystrophy was seen. Lyn kinase has a central role in modulating TLR4-induced inflammation and Syk-induced protection in a 5XFAD mouse model. Our TLIMs ameliorate AD sequalae in an in vitro model of AD and could be a promising therapeutic strategy to treat AD.

Triggering receptors expressed on myeloid cells 2 (TREM2), an immune receptor expressed on myeloid cells, has garnered considerable attention in recent years due to its role in unique signaling pathways and diverse biological functions, including phagocytosis, lipid metabolism, cell survival, and inflammatory responses. Although TREM2 is expressed in various cell types, such as macrophages, dendritic cells (DCs), osteoclasts, and others, where it exhibits context-dependent functional characteristics, it is mainly expressed in macrophages. Notably, TREM2 is implicated in the development and progression of multiple diseases, playing dual and often opposing roles in noncancerous diseases and cancers. This review aims to highlight the pivotal role of TREM2 in macrophages and immune-related diseases, elucidate its underlying mechanisms of action, explore its potential as a clinical diagnostic and prognostic marker, and propose therapeutic strategies targeting TREM2 based on current clinical trial data, providing comprehensive guidance and references for clinical practice.

Atherosclerosis is driven by the expansion of cholesterol-loaded foamy macrophages in the arterial intima. Single-cell RNA sequencing has recently revealed the transcriptional landscape of macrophages in these atherosclerotic plaques and uncovered a population of foamy cell-like myeloid cells expressing triggering receptor expressed on myeloid cells-2 (TREM2)-TREM2hi macrophages. Fundamental research has brought essential insight into the significance of TREM2 for foam macrophage survival and atherosclerosis progression, making TREM2 as a therapeutic target in atherosclerosis possible. This review retraces TREM2's winding route from pure knowledge to therapeutic interventions, as well as the potential feasibility of its clinical application for atherosclerosis.

Demyelinating disorders, characterizing by the loss of myelin integrity, present significant challenges due to their impact on neurological function and lack of effective treatments. Understanding the mechanisms underlying myelin damage is crucial for developing therapeutic strategies. Triggering receptor expressed on myeloid cells 2 (TREM2), a pivotal immune receptor predominantly found on microglial cells, plays essential roles in phagocytosis and lipid metabolism, vital processes in neuroinflammation and immune regulation. Emerging evidence indicates a close relationship between TREM2 and various aspects of myelin sheath dynamics, including maintenance, response to damage, and regeneration. This review provides a comprehensive discussion of TREM2's influence on myelin physiology and pathology, highlighting its therapeutic potential and putative mechanisms in the progression of demyelinating disorders.

Triggering receptor expressed on myeloid cells 2 (TREM2)-expressing macrophages and systemic levels of soluble TREM2 (sTREM2) appear critical in the development of chronic liver disease (CLD) and seem relevant in its detection. The aim of this study was to examine sTREM2 as a marker for early CLD and its potential to predict posthepatectomy liver failure (PHLF) in patients undergoing partial hepatectomy.

sTREM2 was assessed in the plasma of 108 patients undergoing liver resection. Blood was drawn prior to surgery (preop) and on the first and fifth postoperative day.

Preop sTREM2 levels were similar across different indications for resection (p = 0.091). Higher preop sTREM2 levels were associated with advanced hepatic fibrosis (p = 0.030) and PHLF (p = 0.007). Fibrosis-4 index (FIB-4) (p = 0.619) and model for end-stage liver disease (MELD) (p = 0.590) did not show a difference between patients grouped by their CLD. Comparing the AUC from receiver-operating characteristic analysis, sTREM2 (AUC = 0.708) outperformed FIB-4 (AUC = 0.529), MELD (AUC = 0.587), Child-Pugh grading (AUC = 0.570) and LiMAx (liver maximum capacity test) (AUC = 0.516) in predicting PHLF. Similarly, in uni- and multivariate analysis, only sTREM2 proved predictive for PHLF (p = 0.023). High-risk (p = 0.003) and low-risk (p = 0.011) cut-offs for systemic sTREM2 levels could identify patients at risk for adverse outcomes after surgery. Finally, high sTREM2 was associated with decreased overall survival after liver surgery (p <0.001).

Circulating sTREM2 shows sensitivity for early-stage, asymptomatic liver disease, irrespective of the underlying indication for liver surgery. Assessment of CLD via sTREM2 monitoring could improve early detection of CLD and improve outcomes after liver surgery.

Soluble TREM2 (sTREM2) has previously been shown to correlate with the degree of chronic liver disease. We found that even in patients undergoing liver resection, who generally do not suffer from end-stage liver disease, sTREM2 reflects liver fibrosis status and predicts postoperative development of liver dysfunction. This is especially relevant for liver surgeons and patients, as postoperative liver dysfunction is the main reason for postoperative mortality. Our findings are also important for hepatologists, as early detection of liver fibrosis and cirrhosis is paramount for overall patient survival and we can show that even in a cohort with a median model for end-stage liver disease score of 6, sTREM2 is able to distinguish patients based on their liver fibrosis status.

Sepsis is a systemic inflammatory response syndrome triggered by infection, often accompanied by severe coagulopathy, leading to high mortality. Tissue factor (TF) plays a pivotal role in sepsis by promoting both coagulation and inflammation. Recently, TREM2 (Triggering Receptor Expressed on Myeloid cells 2) has emerged as a key regulator of macrophage function, but its specific role in sepsis remains unclear.

An in vitro sepsis model was established by stimulating RAW264.7 cells with 10 μg/mL lipopolysaccharide (LPS) for 6 h, with four groups: Negative Control (NC), NC + LPS, TREM2, and TREM2 + LPS. Inflammatory cytokines and coagulation factors were measured in each group. Cells in the TREM2 and TREM2 + LPS groups were pretreated with TREM2 overexpression plasmid for 48 h. In vivo, mice were assigned to Sham, TREM2, Cecal Ligation and Puncture (CLP), CLP + NC, and CLP + TREM2 groups. Mice in the NC group received macrophages via tail vein injection, while those in the TREM2 and CLP + TREM2 groups received TREM2-overexpressing macrophages. Lung tissue and plasma samples were collected to assess inflammatory cytokines, coagulation factors, and signaling pathway activity.

TREM2 overexpression significantly improved survival, reduced lung inflammation, and alleviated coagulopathy in mice. It increased platelet counts and reduced fibrin deposition. Furthermore, TREM2 inhibited TF release from macrophages by suppressing aberrant activation of the AKT-mTOR signaling pathway, thereby modulating the macrophage inflammatory response.

TREM2 plays a crucial protective role in sepsis-associated coagulopathy, suggesting that it could serve as a potential therapeutic target, providing novel strategies to improve clinical outcomes in sepsis patients.

Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Amyloid-β (Aβ) accumulation and neurofibrillary tangles are two key histological features resulting in progressive and irreversible neuronal loss and cognitive decline. The macrophages of the central nervous system (CNS) belong to the innate immune system and comprise parenchymal microglia and CNS-associated macrophages (CAMs) at the CNS interfaces (leptomeninges, perivascular space and choroid plexus). Microglia and CAMs have received attention as they may play a key role in disease onset and progression e. g., by clearing amyloid beta (Aβ) through phagocytosis. Genome-wide association studies (GWAS) have revealed that human microglia and CAMs express numerous risk genes for AD, further highlighting their potentially critical role in AD pathogenesis. Microglia and CAMs are tightly controlled by environmental factors, such as the host microbiota. Notably, it was further reported that the composition of the gut microbiota differed between AD patients and healthy individuals. Hence, emerging studies have analyzed the impact of gut bacteria in different preclinical mouse models for AD as well as in clinical studies, potentially enabling promising new therapeutic options.

Alzheimer's disease, a significant contributor to dementia, is rapidly becoming a serious healthcare concern in the 21st century. The alarming number of patients with Alzheimer's disease is steadily increasing, which is contributed by the dearth of treatment options. The current treatment for Alzheimer's disease is heavily dependent on symptomatic treatment that has failed to cure the disease despite huge investments in the development of drugs. The clinical treatment of Alzheimer's disease with limited drugs is generally targeted towards the inhibition of N-methyl-d-aspartate receptor and acetylcholine esterase, which only elevate cognition levels for a limited period. Beyond the aforementioned molecular targets, β-amyloid was much explored with little success and thus created a feel and palpable growing emphasis on discovering new putative and novel targets for AD. This has inspired medicinal chemists to explore new targets, including microglia, triggering receptors expressed on myeloid cells 2 (Trem-2), and notum carboxylesterase, to discover new lead compounds. This review explores the functions, pathophysiological roles, and importance of all AD-related targets that address therapeutic and preventive approaches for the treatment and protection of Alzheimer's disease.

Microglia, the resident immune cells of the central nervous system, continuously monitor the brain's microenvironment through their array of specific receptors. Once brain function is altered, microglia are recruited to specific sites to perform their immune functions, including phagocytosis of misfolded proteins, cellular debris, and apoptotic cells to maintain homeostasis. When toxic substances are overproduced, microglia are over-activated to produce large amounts of pro-inflammatory cytokines, which induce chronic inflammatory responses and lead to neurotoxicity. Additionally, microglia can also monitor and protect neuronal function through microglia-neuron crosstalk. Microglia receptors are important mediators for microglia to receive external stimuli, regulate the functional state of microglia, and transmit signals between cells. In this paper, we first review the role of microglia-expressed receptors in the pathogenesis and treatment of Alzheimer's disease; moreover, we emphasize the complexity of targeting microglia for therapeutic interventions in neurodegenerative disorders to inform the discovery of new biomarkers and the development of innovative therapeutics.

The chronic inflammatory condition known as multiple sclerosis (MS) causes inflammation and demyelination in the central nervous system (CNS). The activation of multiple cell types, including the CNS's resident immune cells called microglia, is a component of the immunological response in MS. Recently, the triggering receptor expressed on myeloid cells (TREM) family has emerged as a crucial player in modulating microglial function and subsequent neuroinflammation. Understanding the role of TREM receptors in MS pathogenesis could provide insightful information on how to develop new therapeutic approaches.

The TREM family consists of several receptors, including TREM-1 and TREM-2, which can be expressed on both immune cells, such as myeloid cells and microglia, and non-immune cells. These receptors interact with their respective ligands and regulate signaling pathways, ultimately leading to the control of microglial activation and inflammatory reactions. TREM-2, in particular, has garnered significant interest because of its connection with MS and other neurodegenerative diseases. The activation of microglia through TREM receptors in MS is thought to influence the equilibrium between helpful and detrimental inflammatory responses. TREM receptors can promote the phagocytosis of myelin debris and remove apoptotic cells, thus contributing to tissue repair and regeneration. However, excessive or dysregulated activation of microglia mediated by TREM receptors can lead to the release of pro-inflammatory cytokines and neurotoxic factors, exacerbating neuroinflammation and neurodegeneration in MS.

The emerging role of the TREM family in demyelinating diseases highlights the importance of microglia in disease pathogenesis. Understanding the mechanisms by which TREM receptors modulate microglial function can provide valuable insights into the development of targeted therapies for these disorders. By selectively targeting TREM receptors, it may be possible to harness their beneficial effects on tissue repair while dampening their detrimental pro-inflammatory responses. Further research is warranted to elucidate the precise signaling pathways and ligand interactions involved in TREM-mediated microglial activation, which could uncover novel therapeutic avenues for treating MS and other neuroinflammatory disorders.

The myeloid-specific triggering receptors expressed on myeloid cells 2 (TREM2) is a group of class I receptors expressed in brain microglia plays a decisive role in neurodegenerative diseases such as Alzheimer's disease (AD) and Nasu Hakola disease (NHD). The extracellular domain (ECD) of TREM2 interacts with a wide-range of ligands, yet the molecular mechanism underlying recognition of such ligands to this class I receptor remains underexplored. Herein, we undertook a systematic investigation for exploring the mode of ligand recognition in immunoglobulin-like ectodomain by employing both knowledge-based and machine-learning guided molecular docking approach followed by the state-of-the-art all atoms molecular dynamics (MD) simulations. Besides the known binding site formed by complementarity-determining regions (CDR) 1 and CDR2 loops, which enables the binding of different anionic ligands, our study identifies the presence of second binding site formed by β-strands towards the C-terminal end. We observe a dense network of hydrophobic contacts formed between the explored ligands and CDR loops and β-strands, specifically CDR1, CDR2, β-strand C', loop connecting β-strand D and E, and loop connecting β-strand E and F. Ligand binding in immunoglobulin-like ectodomain increases the conformational flexibility of CDR2 loop, thus most frequently observed pathogenic variants i.e. R47H and R62H in TREM2 may affect the development and progression of AD. Our knowledge-based and machine-learning guided docking and physics-based simulations study unveils deep insights into the endogenous ligand recognition by the positive surface ligand binding site and distant core site pave the way for exploration of other small molecules towards development of novel therapeutics against Alzheimer's disease.

In vitro models play a pivotal role in advancing our understanding of neurodegenerative diseases (NDs) such as Parkinson's and Alzheimer's disease (PD and AD). Traditionally, 2D cell cultures have been instrumental in elucidating the cellular mechanisms underlying these diseases. Cultured cells derived from patients or animal models provide valuable insights into the pathological processes at the cellular level. However, they often lack the native tissue environment complexity, limiting their ability to fully recapitulate their features. In contrast, 3D models offer a more physiologically relevant platform by mimicking the 3D brain tissue architecture. These models can incorporate multiple cell types, including neurons, astrocytes, and microglia, creating a microenvironment that closely resembles the brain's complexity. Bioengineering approaches allow researchers to better replicate cell-cell interactions, neuronal connectivity, and disease-related phenotypes. Both 2D and 3D models have their advantages and limitations. While 2D cultures provide simplicity and scalability for high-throughput screening and basic processes, 3D models offer enhanced physiological relevance and better replicate disease phenotypes. Integrating findings from both model systems can provide a better understanding of NDs, ultimately aiding in the development of novel therapeutic strategies. Here, we review existing 2D and 3D in vitro models for the study of PD and AD.

Cerebrospinal fluid (CSF) β2-microglobulin (β2M) has been demonstrated as an important factor in β-amyloid (Aβ) neurotoxicity and a potential target for Alzheimer's disease (AD). However, more investigation is required to ascertain the relationship between β2M and glial activities in AD pathogenesis.

In this study, 211 participants from the Alzheimer's disease Neuroimaging Initiative (ADNI) with CSF and Plasma β2M, CSF glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), Aβ42, phosphorylated-tau (P-tau) and total tau (T-tau) were divided into four groups, stage 0, 1, 2, and suspected non-AD pathology (SNAP) based on the National Institute on Aging- Alzheimer's Association (NIA-AA) criteria. Multiple linear regression, linear mixed effects models, and causal mediation analyses bootstrapped 10,000 iterations were used to investigate the underlying associations among β2M and CSF biomarkers at baseline and during a longitudinal visit.

CSF β2M concentration decreased with amyloid in stage 1 compared with stage 0 and increased with tau pathology and neurodegeneration in stage 2 and SNAP compared with stage 1. Moreover, CSF β2M level was positively correlated with the Aβ42 (β = 0.230), P-tau (β = 0.564), T-tau (β = 0.603), GFAP (β = 0.552), and sTREM2 (β = 0.641) (all P < 0.001). CSF β2M was only longitudinally correlated with T-tau change. The correlation of CSF β2M with P-tau (proportion = 25.4%, P < 0.001) and T-tau (proportion = 26.7%, P < 0.001) was partially mediated by GFAP in total participants, reproduced in late-life individuals. Furthermore, the astrocyte cascade also partially mediated the pathological relationship between CSF β2M and tau pathology (β2M → GFAP → YKL-40 → P-tau/T-tau, IE: 0.424-0.435, all P < 0.001). Nevertheless, the mediation effects of sTREM2 were not significant. Additionally, there was no association between plasma β2M and CSF biomarkers.

CSF β2M is dynamic in AD pathology and associated with neuroinflammation. CSF GFAP might mediate the association between β2M and tau pathology, complementing the existing research on the effect of β2M in AD pathology and providing a new perspective on treatment.

The occurrence of Alzheimer's disease (AD) can be partially prevented through healthy lifestyles, but the mechanisms associated with AD pathology are unclear.

To explore associations among healthy lifestyle characteristics (HLCs), cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), and AD biomarkers.

From the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, 924 cognitively normal participants were enrolled in this cross-sectional analysis. We defined the following 11 HLCs: appropriate frequencies of coffee and tea consumption, sufficient frequencies of fish and fruit intake, non-social isolation, adequate sleep, regular physical activity, no depression, never smoking, non-hazardous drinking, and well-maintained blood pressure. We categorized participants according to the number of HLCs reported by participants into favorable, intermediate, and unfavorable lifestyle groups. Multiple linear regression was used to investigate the relationship among HLCs, CSF sTREM2, and AD biomarkers. Mediation effects were tested using a causal mediation analysis having 10,000 bootstrap iterations.

Included subjects were with a mean age of 61.8 ± 10.2 years, of which 41.8% were female. Sufficient fish intake (β = -0.164, p = 0.017) and well-maintained blood pressure (β = -0.232, p = 0.006) were significantly correlated with lower CSF sTREM2 levels. A larger number of HLCs were associated with lower CSF T-tau (p = 0.001), P-tau (p = 0.012), and sTREM2 (p = 0.040) levels. CSF sTREM2 partially mediated the association between the number of HLCs and CSF tau pathology (mediating proportion T-tau: 22.4%; P-tau: 25.0%).

HLCs might impact the pathological processes of AD by regulating neuroinflammation.

The Triggering Receptor Expressed on Myeloid cells 2 (TREM-2) has been widely known by its anti-inflammatory activity. It can be activated in response to microbes and tissue damage, leading to phagocytosis, autophagy, cell polarization and migration, counter inflammation, and tissue repair. So far, the receptor has been largely explored in neurodegenerative disorders, however, a growing number of studies have been investigating its contribution in different pathological conditions, including metabolic diseases, in which (resident) macrophages play a crucial role. In this regard, TREM-2 + macrophages have been implicated in the onset and development of obesity, atherosclerosis, and fibrotic liver disease. These macrophages can be detected in the brain, white adipose tissue, liver, and vascular endothelium. In this review we discuss how different murine models have been demonstrating the ability of such cells to contribute to tissue and body homeostasis by phagocytosing cellular debris and lipid structures, besides contributing to lipid homeostasis in metabolic diseases. Therefore, understanding the role of TREM-2 in metabolic disorders is crucial to expand our current knowledge concerning their immunopathology as well as to foster the development of more targeted therapies to treat such conditions.

Microglia, the intrinsic neuroimmune cells residing in the central nervous system (CNS), exert a pivotal influence on brain development, homeostasis, and functionality, encompassing critical roles during both aging and pathological states. Recent advancements in comprehending brain plasticity and functions have spotlighted conspicuous variances between male and female brains, notably in neurogenesis, neuronal myelination, axon fasciculation, and synaptogenesis. Nevertheless, the precise impact of microglia on sex-specific brain cell plasticity, sculpting diverse neural network architectures and circuits, remains largely unexplored. This article seeks to unravel the present understanding of microglial involvement in brain development, plasticity, and function, with a specific emphasis on microglial signaling in brain sex polymorphism. Commencing with an overview of microglia in the CNS and their associated signaling cascades, we subsequently probe recent revelations regarding molecular signaling by microglia in sex-dependent brain developmental plasticity, functions, and diseases. Notably, C-X3-C motif chemokine receptor 1 (CX3CR1), triggering receptors expressed on myeloid cells 2 (TREM2), calcium (Ca2+), and apolipoprotein E (APOE) emerge as molecular candidates significantly contributing to sex-dependent brain development and plasticity. In conclusion, we address burgeoning inquiries surrounding microglia's pivotal role in the functional diversity of developing and aging brains, contemplating their potential implications for gender-tailored therapeutic strategies in neurodegenerative diseases.

Microglia are critical responders to amyloid beta (Aβ) plaques in Alzheimer's disease (AD). Therefore, the therapeutic targeting of microglia in AD is of high clinical interest. While previous investigation has focused on the innate immune receptors governing microglial functions in response to Aβ plaques, how microglial innate immune responses are regulated is not well understood. Interestingly, many of these microglial innate immune receptors contain unique cytoplasmic motifs, termed immunoreceptor tyrosine-based activating and inhibitory motifs (ITAM/ITIM), that are commonly known to regulate immune activation and inhibition in the periphery. In this review, we summarize the diverse functions employed by microglia in response to Aβ plaques and also discuss the innate immune receptors and intracellular signaling players that guide these functions. Specifically, we focus on the role of ITAM and ITIM signaling cascades in regulating microglia innate immune responses. A better understanding of how microglial innate immune responses are regulated in AD may provide novel therapeutic avenues to tune the microglial innate immune response in AD pathology.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2R47H mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH (n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2R47H mice, with increased IBA1 protein in TREM2R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies.

The study of neurodegenerative diseases, particularly tauopathies like Pick's disease (PiD) and Alzheimer's disease (AD), offers insights into the underlying regulatory mechanisms. By investigating epigenomic variations in these conditions, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched non-coding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine-mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database (http://swaruplab.bio.uci.edu/scROAD) to visualize predicted single-cell TF occupancy and regulatory networks.

The nervous and the immune systems undergo a continuous cross talk, starting from early development and continuing throughout adulthood and aging. Defects in this cross talk contribute to neurodevelopmental and neurodegenerative diseases. Microglia are the resident immune cells in the brain that are primarily involved in this bidirectional communication. Among the microglial genes, trem2 is a key player, controlling the functional state of microglia and being at the forefront of many processes that require interaction between microglia and other brain components, such as neurons and oligodendrocytes. The present review focuses on the early developmental window, describing the early brain processes in which TREM2 is primarily involved, including the modulation of synapse formation and elimination, the control of neuronal bioenergetic states as well as the contribution to myelination processes and neuronal circuit formation. By causing imbalances during these early maturation phases, dysfunctional TREM2 may have a striking impact on the adult brain, making it a more sensitive target for insults occurring during adulthood and aging.

Alzheimer's disease (AD) is a progressive disease that causes an impairment of learning and memory. Despite the highly complex pathogenesis of AD, amyloid beta (Aβ) deposition and neurofibrillary tangles (NFTs) formation are the main hallmarks of AD. Neuroinflammation also has a crucial role in the development of AD. As the central nervous system's innate immune cells, microglial cells are activated in AD and induce inflammation by producing pro-inflammatory mediators. However, microglial activation is not always deleterious. M2-activated microglial cells are considered anti-inflammatory cells, which develop neuroprotection. Various approaches are proposed for managing AD, yet no effective therapy is available for this disorder. Considering the potential protective role of M2 microglia in neurodegenerative disorders and the improvement of these disorders by preconditioning approaches, it can be suggested that preconditioning of microglial cells may be beneficial for managing AD progression. Therefore, this study review microglial preconditioning approaches for preventing and improving AD.

Protein aggregation plays a crucial role in the development of several neurodegenerative diseases. It is important to understand the aggregation process for the detection of the onset of these diseases. Alzheimer's Disease (AD) is one of the most prevalent neurodegenerative diseases caused by the aggregation of Aβ-40 and Aβ-42 peptides. The smaller oligomers lead to the formation of protein plaque at the neural membranes leading to memory loss and other disorders. Interestingly, aggregation takes place at the neural membranes, therefore the membrane composition seems to play an important role in the aggregation process. Despite a large number of literatures on the effect of lipid composition on protein aggregation, there are very few concise reviews that highlight the role of membrane composition in protein aggregation. In this review, we have discussed the implication of membrane composition on the aggregation of amyloid beta peptide with a special emphasis on cholesterol. We have further discussed the role of the degree of unsaturation of fatty acids and the participation of apolipoprotein E4 (ApoE4) in the onset of AD.

Alzheimer's disease (AD) is a widespread neurodegenerative condition affecting millions globally. Recent research has implicated variants of the triggering receptor expressed in myeloid cells 2 (TREM2) as risk factors for AD. TREM2, an immunomodulatory receptor on microglial surfaces, plays a pivotal role in regulating microglial activation by association with DNAX-activation protein 12 (DAP12). Despite its significance, the mechanism underlying the formation of the complex between the transmembrane domains (TMDs) of TREM2 and DAP12 remains unclear. This study employs multiscale molecular dynamics (MD) simulations to investigate three TMD complex models, including two derived from experiments and one generated by AlphaFold2. Conducted within a lipid membrane consisting of an 80:20 mixture of phosphatidylcholine (POPC) and cholesterol, our analysis reveals hydrogen-bonding interactions between K26 of TREM2 and D16 of DAP12 in all three models, consistent with previous experimental findings. Our results elucidate the different spatial conformations observed in the models and offer insights into the structure of the TREM2/DAP12 TMD complex. Furthermore, we elucidate the role of charged residues in the assembly structure of the complex within the lipid membrane. These findings enhance our understanding of the molecular mechanism governing TREM2/DAP12 complex formation, providing a foundation for designing novel therapeutic strategies to address AD and other neurodegenerative diseases.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. The etiology of the disease remains largely unknown, but evidence have suggested that the overexpression and aggregation of alpha-synuclein (α-syn) play key roles in the pathogenesis and progression of PD. Mesenchymal stromal cells (MSCs) have been earning attention in this field, mainly due to their paracrine capacity. The bioactive molecules secreted by MSCs, i.e. their secretome, have been associated with enhanced neuronal survival as well as a strong modulatory capacity of the microenvironments where the disease develops. The selection of the appropriate animal model is crucial in studies of efficacy assessment. Given the involvement of α-syn in the pathogenesis of PD, the evidence generated from the use of animal models that develop a pathologic phenotype due to the action of this protein is extremely valuable. Therefore, in this work, we established an animal model based on the viral vector-mediated overexpression of A53T α-syn and studied the impact of the secretome of bone marrow mesenchymal stromal cells MSC(M) as a therapeutic strategy.

Adult male rats were subjected to α-syn over expression in the nigrostriatal pathway to model dopaminergic neurodegeneration. The impact of locally administered secretome treatment from MSC(M) was studied. Motor impairments were assessed throughout the study coupled with whole-region (striatum and substantia nigra) confocal microscopy evaluation of histopathological changes associated with dopaminergic neurodegeneration and glial cell reactivity.

Ten weeks after lesion induction, the animals received secretome injections in the substantia nigra pars compacta (SNpc) and striatum (STR). The secretome used was produced from bone marrow mesenchymal stromal cells MSC(M) expanded in a spinner flask (SP) system. Nine weeks later, animals that received the viral vector containing the gene for A53T α-syn and treated with vehicle (Neurobasal-A medium) presented dopaminergic cell loss in the SNpc and denervation in the STR. The treatment with secretome significantly reduced the levels of α-syn in the SNpc and protected the dopaminergic neurons (DAn) within the SNpc and STR.

Our results are aligned with previous studies in both α-syn Caenorhabditis elegans models, as well as 6-OHDA rodent model, revealing that secretome exerted a neuroprotective effect. Moreover, these effects were associated with a modulation of microglial reactivity supporting an immunomodulatory role for the factors contained within the secretome. This further supports the development of new studies exploring the effects and the mechanism of action of secretome from MSC(M) against α-syn-induced neurotoxicity.

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook.

The corpus callosum-the largest commissural fiber system connecting the two cerebral hemispheres-is considered essential for bilateral sensory integration and higher cognitive functions. Most studies exploring the corpus callosum have examined either the anatomical, physiological, and neurochemical organization of callosal projections or the functional and/or behavioral aspects of the callosal connections after complete/partial callosotomy or callosal lesion. There are no works that address the intrinsic organization of the corpus callosum. We review the existing information on the activities that take place in the commissure in three sections: I) the topographical and neurochemical organization of the intracallosal fibers, II) the role of glia in the corpus callosum, and III) the role of the intracallosal neurons.

Alzheimer disease (AD) is the most prominent form of dementia and has received considerable attention due to its growing burden on economic, healthcare and basic societal infrastructures. The two major neuropathological hallmarks of AD, i.e., extracellular amyloid beta (Aβ) peptide plaques and intracellular hyperphosphorylated Tau neurofibrillary tangles, have been the focus of much research, with an eye on understanding underlying disease mechanisms and identifying novel therapeutic avenues. One often overlooked aspect of AD is how Aβ and Tau may, through indirect and direct mechanisms, affect genome integrity. Herein, we review evidence that Aβ and Tau abnormalities induce excessive genomic stress and impair genome maintenance mechanisms, events that can promote DNA damage-induced neuronal cell loss and associated brain atrophy.

Triggering receptor expressed on myeloid cells 2 (TREM-2), a glycosylated receptor belonging to the immunoglobin superfamily and especially expressed in the myeloid cell lineage, is frequently explained as a reminiscent receptor for both adaptive and innate immunity regulation. TREM-2 is also acknowledged to influence NK cell differentiation via the PI3K and PLCγ signaling pathways, as well as the partial activation or direct inhibition of T cells. Additionally, TREM-2 overexpression is substantially linked to cell-specific functions, such as enhanced phagocytosis, reduced toll-like receptor (TLR)-mediated inflammatory cytokine production, increased transcription of anti-inflammatory cytokines, and reshaped T cell function. Whereas TREM-2-deficient cells exhibit diminished phagocytic function and enhanced proinflammatory cytokines production, proceeding to inflammatory injuries and an immunosuppressive environment for disease progression. Despite the growing literature supporting TREM-2+ cells in various diseases, such as neurodegenerative disorders and cancer, substantial facets of TREM-2-mediated signaling remain inadequately understood relevant to pathophysiology conditions. In this direction, herein, we have summarized the current knowledge on TREM-2 biology and cell-specific TREM-2 expression, particularly in the modulation of pivotal TREM-2-dependent functions under physiopathological conditions. Furthermore, molecular regulation and generic biological relevance of TREM-2 are also discussed, which might provide an alternative approach for preventing or reducing TREM-2-associated deformities. At last, we discussed the TREM-2 function in supporting an immunosuppressive cancer environment and as a potential drug target for cancer immunotherapy. Hence, summarized knowledge of TREM-2 might provide a window to overcome challenges in clinically effective therapies for TREM-2-induced diseases in humans.

Glioblastomas (GBM) are incurable central nervous system (CNS) cancers characterized by substantial myeloid cell infiltration. Whether myeloid cell-directed therapeutic targets identified in peripheral non-CNS cancers are applicable to GBM requires further study. Here, we identify that the critical immunosuppressive target in peripheral cancers, triggering receptor expressed on myeloid cells-2 (TREM2), is immunoprotective in GBM. Genetic or pharmacological TREM2 deficiency promotes GBM progression in vivo. Single-cell and spatial sequencing reveals downregulated TREM2 in GBM-infiltrated myeloid cells. TREM2 negatively correlates with immunosuppressive myeloid and T cell exhaustion signatures in GBM. We further demonstrate that during GBM progression, CNS-enriched sphingolipids bind TREM2 on myeloid cells and elicit antitumor responses. Clinically, high TREM2 expression in myeloid cells correlates with better survival in GBM. Adeno-associated virus-mediated TREM2 overexpression impedes GBM progression and synergizes with anti-PD-1 therapy. Our results reveal distinct functions of TREM2 in CNS cancers and support organ-specific myeloid cell remodeling in cancer immunotherapy.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, marked by the degeneration of dopamine (DA) neurons in the substantia nigra (SN). Current evidence strongly suggests that neuroinflammation, primarily mediated by microglia, contributes to PD pathogenesis. Triggering receptor expressed on myeloid cells 2 (TREM2) might serve as a promising therapeutic target for PD due to its ability to suppress neuroinflammation. Dihydroquercetin (DHQ) is an important natural dihydroflavone and confers apparent anti-inflammatory, antioxidant and anti-fibrotic effects. Recently, DHQ-mediated neuroprotection was exhibited. However, the specific mechanisms of its neuroprotective effects remain incompletely elucidated.

In this study, rat models were utilized to induce damage to DA neurons using lipopolysaccharide (LPS) and 6-hydroxydopamine (6-OHDA) to assess the impacts of DHQ on the loss of DA neurons. Furthermore, DA neuronal MN9D cells and microglial BV2 cells were employed to investigate the function of TREM2 in DHQ-mediated DA neuroprotection. Finally, TREM2 knockout mice were used to investigate whether the neuroprotective effects mediated by DHQ through a mechanism dependent on TREM2.

The main findings demonstrated that DHQ effectively protected DA neurons against neurotoxicity induced by LPS and 6-OHDA and inhibited microglia-elicited neuroinflammation. Meanwhile, DHQ promoted microglial TREM2 signaling activation. Notably, DHQ failed to reduce inflammatory cytokines release and further present neuroprotection from DA neurotoxicity upon TREM2 silencing. Similarly, DHQ didn't exert DA neuroprotection in TREM2 knockout mice.

These findings suggest that DHQ exerted DA neuroprotection by regulating microglia TREM2 activation.

Myeloid cells comprise up to 50% of the total tumor mass in glioblastoma (GBM) and have been implicated in promoting tumor progression and immunosuppression. Modulating the response of myeloid cells to the tumor has emerged as a promising new approach for cancer treatment. In this regard, we focus on the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), which has recently emerged as a novel immune modulator in peripheral tumors.

We studied the TREM2 expression profile in various patient tumor samples and conducted single-cell transcriptomic analysis in both GBM patients and the GL261 mouse glioma model. We utilized multiple mouse glioma models and employed state-of-the-art techniques such as invivo 2-photon imaging, spectrum flow cytometry, and in vitro co-culture assays to study TREM2 function in myeloid cell-mediated phagocytosis of tumor cells, antigen presentation, and response of CD4+ T cells within the tumor hemispheres.

Our research revealed significantly elevated levels of TREM2 expression in brain tumors compared to other types of tumors in patients. TREM2 was predominantly localized in tumor-associated myeloid cells and was highly expressed in nearly all microglia, as well as various subtypes of macrophages. Surprisingly, in preclinical glioma models, TREM2 deficiency did not confer a beneficial effect; instead, it accelerated glioma progression. Through detailed investigations, we determined that TREM2 deficiency impaired the ability of tumor-myeloid cells to phagocytose tumor cells and led to reduced expression of MHCII. This deficiency further significantly decreased the presence of CD4+ T cells within the tumor hemispheres.