Neuroinflammation play an important role in Alzheimer's disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of ...neuroinflammation and its relation with Alzheimer's disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer's disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer's disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable
brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.
From the perspective of regulatory focus theory, the influencing mechanism of pro-environmental behaviors (PEBs) in the private domain on behaviors in the public domain were analyzed by revealing the ...mediating effect of the status quo maintenance and the moderating effect of the prevention focus orientation. The study results show that PEBs in the private domain significantly promote individuals’ PEBs in the public domain. The status quo maintenance partially mediates the relationship between PEBs in the private and public domains. Specifically, individuals with a high-level prevention focus orientation strengthen the relationship between the PEBs in the private domain and the status quo maintenance, and that of the PEBs in the public domain. Therefore, individuals with high-level prevention focus will more likely engage in subsequent PEBs in the public domain after their initial PEBs in the private domain due to their increased status quo maintenance degree. Policymakers and practitioners should pay attention to the prevention-repetition effect and use the PEBs in the private domain to promote those in the public domain.
Diabetes and Alzheimer’s disease (AD) place a significant burden on health care systems in the Western world and its aging populations. These diseases have long been regarded as separate entities; ...however, advanced glycation end products (AGEs) and the receptors for AGEs (RAGE) may be a link between diabetes and AD. In our study, mice injected with AGEs through stereotaxic surgery showed significant AD-like features: behavior showed decreased memory; immunofluorescence showed increased phosphorylated tau and APP. These results suggest links between diabetes and AD. Patients with diabetes are at a higher risk of developing AD, and the possible underlying molecular components of this association are now beginning to emerge.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterized by senile plaques (SPs) caused by amyloid beta (Aβ) deposition and neurofibrillary tangles (NFTs) of abnormal ...hyperphosphorylated tau protein. RAGE is a receptor of advanced glycation end-products (AGEs), which are deposited during vascular dysfunction. It may cause AD by binding Aβ and releasing reactive oxygen species (ROS), which further exacerbates Aβ deposition and eventually leads to SPs and NFTs. As it is involved in early AD, RAGE has the potential to be a more potent biomarker compared to Aβ. While positron emission tomography (PET) provides a way to detect valuable information about the underlying pathological processes many years before the appearance of clinical symptoms, a tracer that targets RAGE is needed to further reveal the role of RAGE in AD pathology and for the early diagnosis of AD. In this review, we have introduced a RAGE-targeting probe called 18F-FPS-ZM1. With probes targeting Aβ and tau protein, the role of 18F-FPS-ZM1 in exploring the pathogenesis of RAGE in AD was verified. Due to its high specificity and affinity for RAGE, 18F-FPS-ZM1 is believed to provide accurate and reliable in vivo data for studying local or whole brain pathological changes. Thus, 18F-FPS-ZM1 could greatly promote the early diagnosis and evaluation of AD and provide a way to reflect the early pathological mechanism of AD.
The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer's disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of ...neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer's disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer's disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models.
microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.
Neutrophils are important components in the innate immune system. Neutrophil hyperactivation is regarded as a characteristic of Alzheimer's disease (AD). But
imaging tools observing neutrophil ...activity in AD dynamically is lacking. This study aimed to identify neutrophil infiltration in AD transgenic mice. We used the AD triple-mutant transgenic mouse model and identified the genotype with RT-PCR. Behavioral experiments including an open-field test, a Morris water maze, and a Y-maze test were performed to evaluate the status of this AD model.
F-AV45,
F-PM-PBB3,
Ga-PEG-cFLFLFK, and
F-DPA714 were synthesized according to previous reports. We employed microPET to detect tracer uptake in the AD model and the control mice at different stages. Western blotting was used to observe the expression of functional proteins. We proved the successful establishment of AD models by RT-PCR, behavioral tests, and
F-AV45 and
F-PM-PBB3 PET imaging. We found an increased neutrophil accumulation in the brains of the AD mice through
Ga-PEG-cFLFLFK PET imaging and Western blot assay. Our studies also demonstrated an elevated level of CAP37, which is produced by neutrophils, in the AD brain, and treatment with CAP37 promoted the expression of Iba1, iNOS, and COX-2 in BV2 cultures. Furthermore, our
F-DPA714 PET imaging studies verified the raised activation of microglia in the brain of transgenic AD mice. Collectively, our findings indicate the increased activity of neutrophils in the brain and heart of AD model mice,
Ga-PEG-cFLFLFK PET imaging represents a sensitive method to observe the status of neutrophils in AD, and infiltrated neutrophils can induce the activation of microglia by releasing CAP37 and blocking the activity of neutrophils may be beneficial for the control of AD progression.
Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease. Synaptic impairment and protein aggregates have been reported in the brains of T2DM models. Here, we assessed ...whether neurodegenerative changes in synaptic vesicle 2 A (SV2A), γ-aminobutyric acid type A (GABAA) receptor, amyloid-β, tau and receptor for advanced glycosylation end product (RAGE) can be detected in vivo in T2DM rats.
Positron emission tomography (PET) using 18FSDM-8 (SV2A), 18Fflumazenil (GABAA receptor), 18Fflorbetapir (amyloid-β), 18FPM-PBB3 (tau), and 18FFPS-ZM1 (RAGE) was carried out in 12-month-old diabetic Zucker diabetic fatty (ZDF) and SpragueDawley (SD) rats. Immunofluorescence staining, Thioflavin S staining, proteomic profiling and pathway analysis were performed on the brain tissues of ZDF and SD rats.
Reduced cortical 18FSDM-8 uptake and cortical and hippocampal 18Fflumazenil uptake were observed in 12-month-old ZDF rats compared to SD rats. The regional uptake of 18Fflorbetapir and 18FPM-PBB3 was comparable in the brains of 12-month-old ZDF and SD rats. Immunofluorescence staining revealed Thioflavin S-negative, phospho-tau-positive inclusions in the cortex and hypothalamus in the brains of ZDF rats and the absence of amyloid-beta deposits. The level of GABAA receptors was lower in the cortex of ZDF rats than SD rats. Proteomic analysis further demonstrated that, compared with SD rats, synaptic-related proteins and pathways were downregulated in the hippocampus of ZDF rats.
These findings provide in vivo evidence for regional reductions in SV2A and GABAA receptor levels in the brains of aged T2DM ZDF rats.
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Non-invasive diagnosis of IDH1 mutation for gliomas has great clinical significance, and PET has natural advantage to detect metabolism, as IDH mutated gliomas share lower glucose consumption.
...Clinical data of patients with gliomas and
F-FDG PET were retrospectively reviewed. Receiver operating characteristic curve (ROC) analysis was conducted, and standard uptake value (SUV) was estimated in combination with grades or IDH1 mutation. The glucose consumption was investigated with U251 cells expressing wild-type or mutated IDH1 by glucose assay. Quantification of glucose was determined by HPLC in clinical tissues. Meanwhile, bioinformatics and western blot were applied to analyze the expression level of metabolic enzymes (e.g. HK1, PKM2, PC) in gliomas.
Seventy-one glioma cases were enrolled, including 30 carrying IDH1 mutation. The sensitivity and specificity dependent on SUV
(3.85) predicting IDH1 mutation reached 73.2 and 86.7%, respectively. The sensitivity and specificity of differentiating grades by SUVmax (3.1) were 92.3 and 64.4%, respectively. Glucose consumption of U251 IDH1 mutant cells (0.209 ± 0.0472 mg/ml) was obviously lower than IDH1wild-type cells (0.978 ± 0.0773 mg/ml, P = 0.0001) and astrocyte controls (0.335 ± 0.0592 mg/ml, P = 0.0451). Meanwhile, the glucose quantity in IDH1mutant glioma samples were significantly lower than those in IDH1 wild-type tissues (1.033 ± 1.19608 vs 6.361 ± 4.3909 mg/g, P = 0.0051). Silico analysis and western blot confirmed that HK1 and PKM2 in IDH1 wild-type gliomas were significantly higher than in IDH1 mutant group, while PC was significantly higher in IDH1 mutant gliomas.
SUV
on PET can predict IDH1 mutation with adequate sensitivity and specificity, as is supported by reduced glucose consumption in IDH1 mutant gliomas.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is ...linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown.
The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay.
We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein.
Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM.
There are a lot of multi-objective optimization problems (MOPs) in the real world, and many multi-objective evolutionary algorithms (MOEAs) have been presented to solve MOPs. However, obtaining ...non-dominated solutions that trade off convergence and diversity remains a major challenge for a MOEA. To solve this problem, this paper designs an efficient multi-objective sine cosine algorithm based on a competitive mechanism (CMOSCA). In the CMOSCA, the ranking relies on non-dominated sorting, and the crowding distance rank is utilized to choose the outstanding agents, which are employed to guide the evolution of the SCA. Furthermore, a competitive mechanism stemming from the shift-based density estimation approach is adopted to devise a new position updating operator for creating offspring agents. In each competition, two agents are randomly selected from the outstanding agents, and the winner of the competition is integrated into the position update scheme of the SCA. The performance of our proposed CMOSCA was first verified on three benchmark suites (i.e., DTLZ, WFG, and ZDT) with diversity characteristics and compared with several MOEAs. The experimental results indicated that the CMOSCA can obtain a Pareto-optimal front with better convergence and diversity. Finally, the CMOSCA was applied to deal with several engineering design problems taken from the literature, and the statistical results demonstrated that the CMOSCA is an efficient and effective approach for engineering design problems.
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