Unraveling How Dysfunction of the Microglial Gene TREM2 Increases Risk for Alzheimer's Disease

A heterozygous single amino acid change in the TREM2 gene significantly increases risk for developing late-onset Alzheimer’s Disease (AD). In the brain, Trem2 is uniquely expressed by microglia, strongly implicating microglia in AD pathogenesis. Trem2 is a receptor with numerous ligands and pleiotropic functions ranging from phagocytosis to inflammation and synapse pruning. There has been a significant amount of research on the consequences of Trem2 deficiency in amyloid mouse models. Trem2-deficient mice exhibit reduced microglial clustering around amyloid-beta plaques and reduced levels of inflammatory transcripts. The consequence of Trem2 deficiency in the context of tau pathology, on the other hand, is not well understood. To address this gap, we investigated the effects of Trem2 haploinsufficiency and deficiency on microglial function in the healthy brain and in the context of tauopathy. We found that removing one copy of Trem2 significantly impaired microglia’s ability to respond to injury in vivo to a greater extent than removing both copies of Trem2. Moreover, Trem2 haploinsufficient mice exhibited an increase in tau load, whereas tau load in Trem2 deficient mice was unimpacted or slightly reduced. The increase in tau load in Trem2 haploinsufficient mice correlated with increased levels of pro-inflammatory transcripts and neurodegeneration. Trem2 deficient mice, on the other hand, exhibited reduced levels of pro-inflammatory transcripts and less neurodegeneration. To determine how a single amino acid change in TREM2 increases risk for AD, we used CRISPR to generate two novel mouse models expressing one copy of wild-type or R47H human TREM2 (R47H-hTREM2) driven by the endogenous mouse Trem2 promoter. We found that R47H-hTREM2 caused aberrant hippocampal synaptic transmission and impaired spatial memory. In the context of tauopathy, it exacerbated spatial learning and memory as well, and resulted in higher levels of pro-inflammatory and disease-associated microglial transcripts. Moreover, R47H-hTREM2 microglia caused transcriptional changes in neurons and oligodendrocytes, pertaining to metabolism and oxidative phosphorylation. Lastly, there was significant overlap between our R47H-hTREM2 mouse model and AD patients with the R47H mutation. The most significant overlap was in oligodendrocyte transcripts related to mitochondrial dysfunction and oxidative phosphorylation. In sum, the work highlighted in this dissertation highlights how losing one copy of a gene can be more detrimental than losing both copies and how a single amino acid change in one cell type in the brain can have widespread non-cell autonomous ramifications resulting in cognitive deficits. Hopefully, the pathways highlighted in this work can help guide the development of therapeutic strategies targeted at microglial dysfunction in AD

ETHNOPHARMACOLOGICAL STUDY OF BRAIN OXIDATIVE STRESS IMPROVING POTENTIAL OF CURCUMIN IN INTOXICATED RATS

Objective: The following study aimed to investigate the efficacy of curcumin at preventing amikacin neurotoxicity Methods: Twenty-four male Wister albino rats were randomly divided into four groups including-G (1): control group includes six rats, they were administered 0.5 ml of saline orally for 14 consecutive days. G (2): includes six rats; they were administered 200 mg/kg curcumin orally for 14 consecutive days. G (3): includes six rats, they were administered 300 mg/kg body weight/day of amikacin intraperitoneally for 14 consecutive days G (4): includes six rats, they were administered 200 mg/kg curcumin orally concurrently with 300 mg/kg body weight/day of amikacin. All animals were kept in the same conditions from feed, heat and humidity. Results: According to the result obtained after sacrification of all animals after the end of 14 d, Results revealed that amikacin at the dose rate of 300 mg/kg b. wt for 14 d induces significant changes in oxidative stress markers compared to the control group, a significant reduction in CAT. SOD. GSH (1.51±0.16, 77.00±0.73 and 84.06±4.42) respectively compared to control (3.63±0.11, 98.48±0.18 and 117.05±0.52) along with a significant increase in MDA activity (219.02±3.34) compared to control group (180.42±0.19), That indicate oxidative stress effect of it. On the beneficial side rats received amikacin 300 mg/kg B. wt I/p concurrently with 200 mg/kg b. wt curcumin for successive 14day result in a significant increase in CAT. SOD. GSH (2.23±0.09,92.00±0.26, 102.25±1.71) and decrease in MDA concentration (139.23±3.89) compared to amikacin treated group levels along with histopathological changes appear in brain tissue in the group treated with amikacin include nuclear pyknosis and degeneration in some neurons in the hippocampus, multiple focal eosinophilic plaque formation in the striatum also this results enhanced by activated caspase-3 expression in the brain tissue following amikacin administration. Conclusion: The present study proved that Oral administration of curcumin at the dose of 200 mg/kg for 14 d concurrently with amikacin significantly mitigates its neurotoxic and oxidative stress effects

ANTIDIABETIC ACTIVITY OF CAFFEIC ACID AND 18Î’-GLYCYRRHETINIC ACID AND ITS RELATIONSHIP WITH THE ANTIOXIDANT PROPERTY

Objective: This study was performed to investigate the antidiabetic effect of caffeic acid and 18 β -glycyrrhetinic acid against diabetic rats.Methods: In this experiment, the animals were divided into five groups. Group I: Normal rats. Group II: diabetic control rats.Group III: diabetic rats treated with 18β-glycyrrhetinic. Group IV: diabetic rats treated with caffeic acid. Group V: diabetic rats treated with 18β-glycyrrhetinic and caffeic acid. Fasting blood glucose, insulin, glutathione reductase (GR), glutathione peroxidase (GPx), total antioxidant (TAO), catalase , and superoxide dismutase (SOD) and malondialdehyde (MDA) were analyzed.Results: Fasting blood glucose and MDA were significantly increased, whereas insuline, GR, GPx, TAO, catalase , SOD were decreased significantly in diabetic rats. Though the diabetic rats treated with caffeic acid and 18β-glycyrrhetinic acid individual exerts beneficial effects in all the biochemical parameters in diabetic rats. The combined treatment with caffeic acid and 18β-glycyrrhetinic acid normalized all the above-mentioned biochemical parameters in diabetic rats.Conclusion: our findings demonstrated that 18β-glycyrrhetinic acid and  caffeic acid either used individually or in combination to diabetic rats have an antidiabetic effect and a good antioxidant property .From the results, the combined dose of 18β-glycyrrhetinic acid and caffeic acid to diabetic rats showed promising antidiabetic effect and antioxidant property compared to individual treatments.Keywords: Diabetes, Caffeic acid, 18β-glycyrrhetinic acid, Streptozotocin, Antioxidant

Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis

Synthesis, antifungal activity and semi-empirical AM1-MO calculations of some new 4-oxo-4H-chromene derivatives

Some new antifungal agents have been prepared through reaction of 4-oxo-4H-chromene-3-carbaldehydes (1a,b) with some active primary amines (2a-e) and amides/thioamides (6a-d) in different conditions. Structures of the products were established on the basis of elemental analysis, IR, 1H NMR, mass spectra and semi-empirical AM1-MO calculations

Bioactive chemical constituents of Curcuma longa L. rhizomes extract inhibit the growth of human hepatoma cell line (HepG2)

The present study was designed to identify the chemical constituents of the methanolic extract of Curcuma longa L. rhizomes and their inhibitory effect on a hepatoma cell line. The methanolic extract was subjected to GC-MS analysis to identify the volatile constituents and the other part of the same extract was subjected to liquid column chromatographic separation to isolate curcumin. The inhibition of cell growth in the hepatoma cell line and the cytopathological changes were studied. GC-MS analysis showed the presence of fifty compounds in the methanolic extract of C. longa. The major compounds were ar-turmerone (20.50 %), β-sesquiphellandrene (5.20 %) and curcumenol (5.11 %). Curcumin was identified using IR, 1H and 13C NMR. The inhibition of cell growth by curcumin (IC50 = 41.69 ± 2.87 µg mL–1) was much more effective than that of methanolic extract (IC50 = 196.12 ± 5.25 µg mL–1). Degenerative and apoptotic changes were more evident in curcumin-treated hepatoma cells than in those treated with the methanol extract. Antitumor potential of the methanolic extract may be attributed to the presence of sesquiterpenes and phenolic constituents including curcumin (0.051 %, 511.39 µg g–1 dried methanol extract) in C. longa rhizomes

Electrical power output prediction of combined cycle power plants using a recurrent neural network optimized by waterwheel plant algorithm

It is difficult to analyze and anticipate the power output of Combined Cycle Power Plants (CCPPs) when considering operational thermal variables such as ambient pressure, vacuum, relative humidity, and temperature. Our data visualization study shows strong non-linearity in the experimental data. We observe that CCPP energy production increases linearly with temperature but not pressure. We offer the Waterwheel Plant Algorithm (WWPA), a unique metaheuristic optimization method, to fine-tune Recurrent Neural Network hyperparameters to improve prediction accuracy. A robust mathematical model for energy production prediction is built and validated using anticipated and experimental data residuals. The residuals’ uniformity above and below the regression line suggests acceptable prediction errors. Our mathematical model has an R-squared value of 0.935 and 0.999 during training and testing, demonstrating its outstanding predictive accuracy. This research provides an accurate way to forecast CCPP energy output, which could improve operational efficiency and resource utilization in these power plants

AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation

The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD

Unraveling How Dysfunction of the Microglial Gene TREM2 Increases Risk for Alzheimer's Disease

A heterozygous single amino acid change in the TREM2 gene significantly increases risk for developing late-onset Alzheimer’s Disease (AD). In the brain, Trem2 is uniquely expressed by microglia, strongly implicating microglia in AD pathogenesis. Trem2 is a receptor with numerous ligands and pleiotropic functions ranging from phagocytosis to inflammation and synapse pruning. There has been a significant amount of research on the consequences of Trem2 deficiency in amyloid mouse models. Trem2-deficient mice exhibit reduced microglial clustering around amyloid-beta plaques and reduced levels of inflammatory transcripts. The consequence of Trem2 deficiency in the context of tau pathology, on the other hand, is not well understood. To address this gap, we investigated the effects of Trem2 haploinsufficiency and deficiency on microglial function in the healthy brain and in the context of tauopathy. We found that removing one copy of Trem2 significantly impaired microglia’s ability to respond to injury in vivo to a greater extent than removing both copies of Trem2. Moreover, Trem2 haploinsufficient mice exhibited an increase in tau load, whereas tau load in Trem2 deficient mice was unimpacted or slightly reduced. The increase in tau load in Trem2 haploinsufficient mice correlated with increased levels of pro-inflammatory transcripts and neurodegeneration. Trem2 deficient mice, on the other hand, exhibited reduced levels of pro-inflammatory transcripts and less neurodegeneration. To determine how a single amino acid change in TREM2 increases risk for AD, we used CRISPR to generate two novel mouse models expressing one copy of wild-type or R47H human TREM2 (R47H-hTREM2) driven by the endogenous mouse Trem2 promoter. We found that R47H-hTREM2 caused aberrant hippocampal synaptic transmission and impaired spatial memory. In the context of tauopathy, it exacerbated spatial learning and memory as well, and resulted in higher levels of pro-inflammatory and disease-associated microglial transcripts. Moreover, R47H-hTREM2 microglia caused transcriptional changes in neurons and oligodendrocytes, pertaining to metabolism and oxidative phosphorylation. Lastly, there was significant overlap between our R47H-hTREM2 mouse model and AD patients with the R47H mutation. The most significant overlap was in oligodendrocyte transcripts related to mitochondrial dysfunction and oxidative phosphorylation. In sum, the work highlighted in this dissertation highlights how losing one copy of a gene can be more detrimental than losing both copies and how a single amino acid change in one cell type in the brain can have widespread non-cell autonomous ramifications resulting in cognitive deficits. Hopefully, the pathways highlighted in this work can help guide the development of therapeutic strategies targeted at microglial dysfunction in AD