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

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

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

Diffusion adaptation over networks of particles subject to Brownian fluctuations

This work investigates the influence of diffusion adaptation on the behavior of networks of micro-organisms that are subject to Brownian fluctuations in the motion of their constituent agents. The organisms are assumed to share information, usually through chemical signaling. The information may signal the direction of a target (such as a foreign body) towards which the cells need to migrate. The sharing of information enables the nodes to bias the probabilities of their random walks in favor of the desired direction of motion. It is verified that the adaptive diffusion of direction information enhances the foraging and tracking ability of the cells

Al-Biruni Earth Radius Optimization Based Algorithm for Improving Prediction of Hybrid Solar Desalination System

The performance of a hybrid solar desalination system is predicted in this work using an enhanced prediction method based on a supervised machine-learning algorithm. A humidification–dehumidification (HDH) unit and a single-stage flashing evaporation (SSF) unit make up the hybrid solar desalination system. The Al-Biruni Earth Radius (BER) and Particle Swarm Optimization (PSO) algorithms serve as the foundation for the suggested algorithm. Using experimental data, the BER–PSO algorithm is trained and evaluated. The cold fluid and injected air volume flow rates were the algorithms’ inputs, and their outputs were the hot and cold fluids’ outlet temperatures as well as the pressure drop across the heat exchanger. Both the volume mass flow rate of hot fluid and the input temperatures of hot and cold fluids are regarded as constants. The results obtained show the great ability of the proposed BER–PSO method to identify the nonlinear link between operating circumstances and process responses. In addition, compared to the other analyzed models, it offers better statistical performance measures for the prediction of the outlet temperature of hot and cold fluids and pressure drop values

Correlation of FXIII Val34Leu Polymorphism with Decreased Risk of Myocardial Infarction in Egypt

Aim: Factor XIII is a transglutaminase that crosslinks fibrin in the last steps of the coagulation process. A few polymorphic sites have been identified in this gene, one of them being a point mutation (FXIII Val34Leu), leading to an amino acid change of valine to leucine. Several studies were published on the association between FXIII 34Leu allele and a decreased incidence of myocardial infarction (MI) with high controversy results dependent on the population. The aim of our study was to further investigate the possible protective role of the FXIII 34Leu allele polymorphism against acute MI in Egyptian patients. Study Design: Clinical examination by cardiologist specialists, blood test for biochemical markers and DNA genotyping using specific molecular sensing probes in Real Time PCR. Place and Duration of Study: Patients were recruited from consecutive admission to the coronary care unit, Suez Canal University Hospital, Ismailia, Egypt. Material and Methods: Total 107 subjects were recruited and subdivided into two main groups; patients (82) and control group (25). On admission, the following data were fulfilled: age, smoking, history of Diabetes Mellitus (DM) and Hypertension (HTN), family history of MI. Clinical examination: Blood pressure and Body Mass Index calculation were done and for patients a short outcome prognosis was done using left ventricular Ejection Fraction (EF). Routine laboratory investigations for recruited groups including fasting and postprandial glucose level, Triglycerides, total Cholesterol, HDL-C and LDLC were carried out. Factor XIII Val34Leu was genotyped for all the recruited subjects using site specific molecular probes in real time PCR. Results: Obtained data were analyzed using OD and CI values, Pearson correlation coefficient Inter-correlations and Regression analysis model that showed insignificant association between FXIII Val34Leu polymorphism and MI patients. Conclusion: FXIII 34Leu variant has no association with reduced incidence of myocardial infarction in Egyptian patients