What do the conflicting findings in the trem2 transgenetic mouse model tell us? A systematic review of the role of TREM2 in Alzheimer's disease.

BACKGROUND: Given the established genetic linkage between triggering receptors expressed on myeloid cells 2 (TREM2) and Alzheimer's disease (AD), an expanding research body has delved into the intricate role of TREM2 within the AD context. However, a conflicting landscape of outcomes has emerged from both in vivo and in vitro investigations. This study aimed to elucidate the multifaceted nuances and gain a clearer comprehension of the role of TREM2. METHODS: PubMed database was searched spanning from its inception to January 2022. The search criteria took the form of ("Alzheimer's disease" OR "AD") AND ("transgenic mice model" OR "transgenic mouse model") AND ("Triggering receptor expressed on myeloid cells" OR "TREM2"). Inclusion criteria consisted of the following: (1) publication of original studies in English; (2) utilization of transgenic mouse models for AD research; and (3) reports addressing the subject of TREM2. RESULTS: A total of 43 eligible articles were identified. Our analysis addresses four pivotal queries concerning the interrelation of TREM2 with microglial function, Aß accumulation, tau pathology, and inflammatory processes. However, the diverse inquiries posed yielded inconsistent responses. Nevertheless, the inconsistent roles of TREM2 within these AD mouse models potentially hinge upon factors such as age, sex, brain region, model type, and detection methodologies. CONCLUSIONS: This review substantiates the evolving understanding of TREM2's disease progression-dependent impacts. Furthermore, it reviews the interplay between TREM2 and its effects across diverse tissues and temporal stages.

Integrative Metabolomics and Whole Transcriptome Sequencing Reveal Role for TREM2 in Metabolism Homeostasis in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells-2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown. Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1-TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1-TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression. Our results prompt further studies of the interactions among TREM2, LPL, glucolipid metabolism, and sphingolipid metabolism in AD to identify new diagnostic and treatment strategies.

Alterations of Audiovisual Integration in Alzheimer's Disease.

Audiovisual integration is a vital information process involved in cognition and is closely correlated with aging and Alzheimer's disease (AD). In this review, we evaluated the altered audiovisual integrative behavioral symptoms in AD. We further analyzed the relationships between AD pathologies and audiovisual integration alterations bidirectionally and suggested the possible mechanisms of audiovisual integration alterations underlying AD, including the imbalance between energy demand and supply, activity-dependent degeneration, disrupted brain networks, and cognitive resource overloading. Then, based on the clinical characteristics including electrophysiological and imaging data related to audiovisual integration, we emphasized the value of audiovisual integration alterations as potential biomarkers for the early diagnosis and progression of AD. We also highlighted that treatments targeted audiovisual integration contributed to widespread pathological improvements in AD animal models and cognitive improvements in AD patients. Moreover, investigation into audiovisual integration alterations in AD also provided new insights and comprehension about sensory information processes.

Crosstalk between peripheral immunity and central nervous system in Alzheimer's disease.

The significance of peripheral immunity in the pathogenesis and progression of Alzheimer's diseases (AD) has been recognized. Brain-infiltrated peripheral immune components transporting across the blood-brain barrier (BBB) may reshape the central immune environment. However, mechanisms of how these components open the BBB for AD occurrence and development and correlations between peripheral and central immunity have not been fully explored. Herein, we formulate a hypothesis whereby peripheral immunity as a critical factor allows AD to progress. Peripheral central immune cell crosstalk is associated with early AD pathology and related risk factors. The damaged BBB permits peripheral immune cells to enter the central immune system to deprive its immune privilege promoting the progression toward developing AD. This review summarizes the influences of risk factors on peripheral immunity, alongside their functions, highlighting the concept of peripheral and central immunity as an integrated system in AD pathogenesis, which has received scant attention before.

Unsupervised machine learning model to predict cognitive impairment in subcortical ischemic vascular disease.

INTRODUCTION: It is challenging to predict which patients who meet criteria for subcortical ischemic vascular disease (SIVD) will ultimately progress to subcortical vascular cognitive impairment (SVCI). METHODS: We collected clinical information, neuropsychological assessments, T1 imaging, diffusion tensor imaging, and resting-state functional magnetic resonance imaging from 83 patients with SVCI and 53 age-matched patients with SIVD without cognitive impairment. We built an unsupervised machine learning model to isolate patients with SVCI. The model was validated using multimodal data from an external cohort comprising 45 patients with SVCI and 32 patients with SIVD without cognitive impairment. RESULTS: The accuracy, sensitivity, and specificity of the unsupervised machine learning model were 86.03%, 79.52%, and 96.23% and 80.52%, 71.11%, and 93.75% for internal and external cohort, respectively. DISCUSSION: We developed an accurate and accessible clinical tool which requires only data from routine imaging to predict patients at risk of progressing from SIVD to SVCI. HIGHLIGHTS: Our unsupervised machine learning model provides an accurate and accessible clinical tool to predict patients at risk of progressing from subcortical ischemic vascular disease (SIVD) to subcortical vascular cognitive impairment (SVCI) and requires only data from imaging routinely used during the diagnosis of suspected SVCI. The model yields good accuracy, sensitivity, and specificity and is portable to other cohorts and to clinical practice to distinguish patients with SIVD at risk for progressing to SVCI. The model combines assessment of diffusion tensor imaging and functional magnetic resonance imaging measures in patients with SVCI to analyze whether the "disconnection hypothesis" contributes to functional and structural changes and to the clinical presentation of SVCI.

TREM2 and Microglia Contribute to the Synaptic Plasticity: from Physiology to Pathology.

Synapses are bridges for information transmission in the central nervous system (CNS), and synaptic plasticity is fundamental for the normal function of synapses, contributing substantially to learning and memory. Numerous studies have proven that microglia can participate in the occurrence and progression of neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), by regulating synaptic plasticity. In this review, we summarize the main characteristics of synapses and synaptic plasticity under physiological and pathological conditions. We elaborate the origin and development of microglia and the two well-known microglial signaling pathways that regulate synaptic plasticity. We also highlight the unique role of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia-mediated regulation of synaptic plasticity and its relationship with AD. Finally, we propose four possible ways in which TREM2 is involved in regulating synaptic plasticity. This review will help researchers understand how NDDs develop from the perspective of synaptic plasticity.

Retinal Examinations Provides Early Warning of Alzheimer's Disease.

Patients with Alzheimer's disease have difficulty maintaining independent living abilities as the disease progresses, causing an increased burden of care on family caregivers and the healthcare system and related financial strain. This patient group is expected to continue to expand as life expectancy climbs. Current diagnostics for Alzheimer's disease are complex, unaffordable, and invasive without regard to diagnosis quality at early stages, which urgently calls for more technical improvements for diagnosis specificity. Optical coherence tomography or tomographic angiography has been shown to identify retinal thickness loss and lower vascular density present earlier than symptom onset in these patients. The retina is an extension of the central nervous system and shares anatomic and functional similarities with the brain. Ophthalmological examinations can be an efficient tool to offer a window into cerebral pathology with the merit of easy operation. In this review, we summarized the latest observations on retinal pathology in Alzheimer's disease and discussed the feasibility of retinal imaging in diagnostic prediction, as well as limitations in current retinal examinations for Alzheimer's disease diagnosis.

TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.

The Specific Mechanism of TREM2 Regulation of Synaptic Clearance in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Synaptic dysfunction is an integral feature of AD pathophysiology and a significant factor in early cognitive impairment in AD. Microglia, which are intrinsic immune cells in the central nervous system, play important regulatory roles in the process of synapse formation. Microglia can refine synaptic connections through synaptic clearance to ensure accurate synaptic transmission. Synaptic clearance is not only existed during central nervous system development but also aberrantly activated during AD pathology. However, the mechanisms of synaptic clearance in AD remain to be investigated. TREM2 is involved in the synaptic clearance of microglia, acting alone or with other molecules, such as apolipoprotein E (APOE). In addition, C1q is essential for microglia-mediated synaptic clearance. In this review, we systematically summarized the potential mechanisms of microglia involved in synaptic clearance, comprehensively reviewed the role of TREM2 in microglia regulating synaptic clearance and proposed our hypothesis that TREM2 interacts with APOE and C1q to promote synaptic clearance. This review provides new insights into the role of TREM2 regulation in microglia synaptic clearance and provides potential prospects for the treatment of AD.

Five Major Psychiatric Disorders and Alzheimer's Disease: A Bidirectional Mendelian Randomization Study.

BACKGROUND: Extensive studies put forward the association between Alzheimer's disease (AD) and psychiatric disorders; however, it remains unclear whether these associations are causal. OBJECTIVE: We aimed to assess the potential causal relationship between major psychiatric disorders and AD. METHODS: A bidirectional two-sample Mendelian randomization (MR) was applied to evaluate potential causality between five psychiatric disorders and AD by selecting the single-nucleotide polymorphisms from the genome-wide association studies as instrumental variables. Inverse-variance weighted (IVW) method was used as the main analyzing approach to estimate possible causal effects, alternative methods including MR-Egger, the MR pleiotropy residual sum and outlier, and leave-one-out analysis method were implemented as sensitivity analyzing approaches to ensure the robustness of results. RESULTS: All forward and reverse MR analyses consistently suggested absent causal relations between psychiatric disorders and AD risk [forward IVW: ORADHD, 1.030, 95% CI, 0.908-1.168, p = 0.674; ORanxiety disorders, 0.904, 95% CI, 0.722-1.131, p = 0.377; ORASD, 0.973, 95% CI, 0.746-1.272, p = 0.846; ORBIP, 1.033, 95% CI, 0.925-1.153, p = 0.564; and ORschizophrenia, 1.039, 95% CI, 0.986-1.095, p = 0.156; reverse IVW: ORADHD, 0.993, 95% CI, 0.954-1.034, p = 0.746; ORanxiety disorders, 1.000, 95% CI, 0.999-1.000, p = 0.898; ORASD, 1.001, 95% CI, 0.962-1.042, p = 0.949; ORBIP, 0.997, 95% CI, 0.966-1.028, p = 0.831; and ORschizophrenia, 1.013, 95% CI, 0.978-1.051, p = 0.466]. CONCLUSION: There is no significant evidence supporting the causal association between the five major psychiatric disorders and AD.

Lipid Metabolism in the Development and Progression of Vascular Cognitive Impairment: A Systematic Review.

Background: Vascular cognitive impairment (VCI) is a major public health problem. The current diagnosis of VCI is made based on the assessment of clinical symptoms and neuropsychological measurements, and is supported by neuroimaging. These methods are both time-consuming and expensive, which leads to needs for alternative biomarkers for VCI. Metabolomics is an emerging and powerful tool to discover of new biomarkers of disease, which can investigate variations in different metabolic processes such as lipid, since the brain is highly enriched in lipids and that lipid changes may lead to pathology in the brain. Vascular cognitive impairment is vulnerable to the disturbance of lipid metabolism. Furthermore, blood samples, which could be identified as reliable clinical biomarkers are relatively convenient to obtain and provide a non-invasive assessment. Therefore, our study aims to understand whether peripheral lipid biomarkers can be used as diagnostic biomarkers and monitor the progression of VCI. Methods: We systematically searched the PubMed, Embase, CNKI, and VIP databases to find VCI and lipid metabolism in reports from inception through February 2021. Studies meeting the following criteria were eligible: (1) original studies in humans; (2) lipid metabolites in blood; (3) reports of VCI. Results: Through our review, nine original articles were eligible. Blood-based metabolites that might be potential biomarkers were identified. Most of them including PC, PE, Cers, and ChEs were significantly lower, while elevation of FAs and DGs were associated with VCI. Most importantly, these blood-based metabolites might be proposed as potential biomarkers for VCI, which provides direction for further validation. Discussion and Conclusion: To the best of our knowledge, this is the first systemic review concerning the relationship of lipid metabolism and VCI. It identifies potential biomarkers and provides insights into the disease pathobiology. However, more advanced studies and researches on a lipidomic platform must be done to understand the exact pathology behind and identify potential lipid biomarkers, which might help achieve the goal of discovering novel therapeutics.

TREM2, microglia, and Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) has been suggested to play a crucial role in Alzheimer's disease (AD) pathogenesis, as revealed by genome-wide association studies (GWAS). Since then, rapidly increasing literature related to TREM2 has focused on elucidating its role in AD pathology. In this review, we summarize our understanding of TREM2 biology, explore TREM2 functions in microglia, address the multiple mechanisms of TREM2 in AD, and raise key questions for further investigations to elucidate the detailed roles and molecular mechanisms of TREM2 in microglial responses. A major breakthrough in our understanding of TREM2 is based on our hypothesis suggesting that TREM2 may act as a multifaceted player in microglial functions in AD brain homeostasis. We conclude that TREM2 can not only influence microglial functions in amyloid and tau pathologies but also participate in inflammatory responses and metabolism, acting alone or with other molecules, such as apolipoprotein E (APOE). This review provides novel insight into the broad role of TREM2 in microglial function in AD and enables us to develop new strategies aimed at the immune system to treat AD pathogenesis.

Gene mutations associated with early onset familial Alzheimer's disease in China: An overview and current status.

BACKGROUND: Mutations of three causative genes, namely presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP), have been identified as the major causes of early-onset familial Alzheimer's disease (EOFAD). The prevalence of causative gene mutations in patients with EOFAD has been reported in previous studies worldwide but remains unclear in China. The patients with these known mutations always show considerable clinical phenotypic variability. However, to date, there have been no detailed descriptions of the clinical phenotypes associated with these Chinese EOFAD mutations. Thus, the aim of this study was to describe all of the known mutations in three EOFAD causative genes and genotype-phenotype correlations in Chinese patients with EOFAD. METHOD: We systematically searched the PubMed, MEDLINE, CNKI, VIP, and WAN-FANG databases to find Chinese EOFAD mutations in reports from inception through May 2020. RESULT: We identified 31 studies reporting mutations of three causative genes in China. 10 mutations in APP gene, 27 mutations in PSEN1 gene and six mutations in PSEN2 were discovered in Chinese EOFAD. This review summarized all these probably pathogenic mutations as well as its clinical features. To the best of our knowledge, this is the first systemic review of causative gene mutations in patients with EOFAD in China. CONCLUSION: The analysis of the genetic and clinical phenotype correlations in this review supports the idea that the clinical phenotype might be influenced by specific genetic defects. It also suggests genetic testing and genotype-phenotype correlations are important for the accurate diagnosis and for understanding disease-associated pathways and might also improve disease therapy and prevention.