Classification of asbestos and their nonasbestiform analogues using FTIR and multivariate data analysis.

This study presents a possible application of Fourier transform infrared (FTIR) spectrometry and multivariate data analysis, principal component analysis (PCA), and partial least squares-discriminant analysis (PLS-DA) for classifying asbestos and their nonasbestiform analogues. The objectives of the study are: 1) to classify six regulated asbestos types and 2) to classify between asbestos types and their nonasbestiform analogues. The respirable fraction of six regulated asbestos types and their nonasbestiform analogues were prepared in potassium bromide pellets and collected on polyvinyl chloride membrane filters for FTIR measurement. Both PCA and PLS-DA classified asbestos types and their nonasbestiform analogues on the score plots showed a very distinct clustering of samples between the serpentine (chrysotile) and amphibole groups. The PLS-DA model provided ∼95% correct prediction with a single asbestos type in the sample, although it did not provide all correct predictions for all the challenge samples due to their inherent complexity and the limited sample number. Further studies are necessary for a better prediction level in real samples and standardization of sampling and analysis procedures.

Neuromodulation of the anterior thalamus: Current approaches and opportunities for the future.

The role of thalamocortical circuits in memory has driven a recent burst of scholarship, especially in animal models. Investigating this circuitry in humans is more challenging. And yet, the development of new recording and stimulation technologies deployed for clinical indications has created novel opportunities for data collection to elucidate the cognitive roles of thalamic structures. These technologies include stereoelectroencephalography (SEEG), deep brain stimulation (DBS), and responsive neurostimulation (RNS), all of which have been applied to memory-related thalamic regions, specifically for seizure localization and treatment. This review seeks to summarize the existing applications of neuromodulation of the anterior thalamic nuclei (ANT) and highlight several devices and their capabilities that can allow cognitive researchers to design experiments to assay its functionality. Our goal is to introduce to investigators, who may not be familiar with these clinical devices, the capabilities, and limitations of these tools for understanding the neurophysiology of the ANT as it pertains to memory and other behaviors. We also briefly cover the targeting of other thalamic regions including the centromedian (CM) nucleus, dorsomedial (DM) nucleus, and pulvinar, with associated potential avenues of experimentation.

Comparison of in-person and synchronous remote musculoskeletal exam using augmented reality and haptics: A pilot study.

INTRODUCTION: Utilization of telemedicine for health care delivery increased rapidly during the coronavirus disease 2019 (COVID-19) pandemic. However, physical examination during telehealth visits remains limited. A novel telerehabilitation system-The Augmented Reality-based Telerehabilitation System with Haptics (ARTESH)-shows promise for performing synchronous, remote musculoskeletal examination. OBJECTIVE: To assess the potential of ARTESH in remotely examining upper extremity passive range of motion (PROM) and maximum isometric strength (MIS). DESIGN: In this cross-sectional pilot study, we compared the in-person (reference standard) and remote evaluations (ARTESH) of participants' upper extremity PROM and MIS in 10 shoulder and arm movements. The evaluators were blinded to each other's results. SETTING: Participants underwent in-person evaluations at a Veterans Affairs hospital's outpatient Physical Medicine and Rehabilitation (PM&R) clinic, and underwent remote examination using ARTESH with the evaluator located at a research lab 30 miles away, connected via a high-speed network. PATIENTS: Fifteen participants with upper extremity pain and/or weakness. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Inter-rater agreement between in-person and remote evaluations on 10 PROM and MIS movements and presence/absence of pain with movement was calculated. RESULTS: The highest inter-rater agreements were noted in shoulder abduction and protraction PROM (kappa (κ) = 0.44, confidence interval (CI): -0.1 to 1.0), and in elbow flexion, shoulder abduction, and shoulder protraction MIS (κ = 0.63, CI: 0 to 1.0). CONCLUSIONS: This pilot study suggests that synchronous tele-physical examination using the ARTESH system with augmented reality and haptics has the potential to provide enhanced value to existing telemedicine platforms. With the additional technological and procedural improvements and with an adequately powered study, the accuracy of ARTESH-enabled remote tele-physical examinations can be better evaluated.

Monitoring Worker Exposure to Respirable Crystalline Silica: Application for Data-driven Predictive Modeling for End-of-Shift Exposure Assessment.

In the ever-expanding complexities of the modern-day mining workplace, the continual monitoring of a safe and healthy work environment is a growing challenge. One specific workplace exposure concern is the inhalation of dust containing respirable crystalline silica (RCS) which can lead to silicosis, a potentially fatal lung disease. This is a recognized and regulated health hazard, commonly found in mining. The current methodologies to monitor this type of exposure involve distributed sample collection followed by costly and relatively lengthy follow-up laboratory analysis. To address this concern, we have investigated a data-driven predictive modeling pipeline to predict the amount of silica deposition quickly and accurately on a filter within minutes of sample collection completion. This field-based silica monitoring technique involves the use of small, and easily deployable, Fourier transform infrared (FTIR) spectrometers used for data collection followed by multivariate regression methodologies including Principal Component Analysis (PCA) and Partial Least Squares (PLS). Given the complex nature of respirable dust mixtures, there is an increasing need to account for multiple variables quickly and efficiently during analysis. This analysis consists of several quality control steps including data normalization, PCA and PLS outlier detection, as well as applying correction factors based on the sampler and cassette used for sample collection. While outside the scope of this article to test, these quality control steps will allow for the acceptance of data from many different FTIR instruments and sampling types, thus increasing the overall useability of this method. Additionally, any sample analyzed through the model and validated using a secondary method can be incorporated into the training dataset creating an ever-growing, more robust predictive model. Multivariant predictive modeling has far-reaching implications given its speed, cost, and scalability compared to conventional approaches. This contribution presents the application of PCA and PLS as part of a computational pipeline approach to predict the amount of a deposited mineral of interest using FTIR data. For this specific application, we have developed the model to analyze RCS, although this process can be implemented in the analysis of any IR-active mineral, and this pipeline applied to any FTIR data.

Functional neuroanatomy of cognition in Parkinson's disease.

While cognitive dysfunction in Parkinson's disease (PD) is increasingly recognized as a progressive symptom of the underlying neurodegenerative disease, our understanding of the functional and structural anatomic changes underlying these cognitive changes remains incomplete. Like the motor system, research point to a complex interplay between multiple parallel yet interconnected networks or circuits that are affected in PD and give rise to cognitive symptomatology. These circuits are most often studied in the context of disorders of executive function, and tightly linke to frontal lobe dysfunction. While the tasks employed vary across studies and it is often unclear whether differences in anatomy and function are causal or compensatory, the literature points to several key circuits that seem to be uniquely impaired in PD patients with cognitive dysfunction. This chapter reviews four of these circuits including the frontostriatal, frontoparietal, mesocortical, and noradrenergic circuits. By gaining a better understanding of the functional neuroanatomy of these circuits, we begin to develop a more comprehensive and unifed picture of how they to account for the pathophysiology of cognitive dysfunction in PD.

Psychosis in Alzheimer's Disease Is Associated With Increased Excitatory Neuron Vulnerability and Post-transcriptional Mechanisms Altering Synaptic Protein Levels.

Alzheimer's disease with psychosis (AD+P) is a heritable phenotypic variant of the disease which is associated with more rapid cognitive deterioration compared to Alzheimer's disease without psychosis (AD-P). Cognitive decline in AD correlates with synapse loss, and our previous studies suggest that those with AD+P have a differentially affected synaptic proteome relative to those with AD-P. In this study, we utilized RNA-sequencing of dorsolateral prefrontal cortex (DLPFC) in a cohort of 80 AD cases to evaluate novel transcriptomic signatures that may confer risk of psychosis in AD. We found that AD+P was associated with a 9% reduction in excitatory neuron proportion compared to AD-P [Mean (SD) AD+P 0.295 (0.061); AD-P 0.324 (0.052), p = 0.026]. mRNA levels contributed only modestly to altered synaptic proteins in AD+P relative to AD-P. Instead, network analysis identified altered expression of gene modules from protein ubiquitination, unfolded protein response, eukaryotic initiation factor 2 (EIF2) signaling and endoplasmic reticulum stress pathways in AD+P. We previously found that neuropathologies account for ~18% of the variance in the occurrence of psychosis in AD. Further inclusion of cell type proportions and differentially expressed modules increased the percent of the variance in psychosis occurrence accounted for in our AD cohort to 67.5%.

Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer's disease.

APOE and Trem2 are major genetic risk factors for Alzheimer's disease (AD), but how they affect microglia response to Aß remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aß, facilitate Aß uptake, and ameliorate Aß effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aß uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aß mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD.

Bertolotti Syndrome With Articulated L5 Transverse Process Causing Intractable Back Pain: Surgical Video Showcasing a Minimally Invasive Approach for Disconnection: 2-Dimensional Operative Video.

Bertolotti syndrome is a commonly missed cause of intractable back pain that affects 4% to 8% of the general population. It involves the congenital malformation of a transitional lumbosacral vertebra, with total or partial and unilateral or bilateral transverse process (TP) fusion or articulation to the sacrum. The pain can be debilitating, and the tethering of the spine to the sacrum can encourage deformity formation in the coronal plane and lead to early degenerative changes, especially if present only unilaterally. We present the case of a 24-yr-old woman with no notable prior medical history who presented with years of lower axial back pain radiating to her thighs, which limited her activities of daily living and was resistant to conservative management. Her imaging showed an abnormally large left L5 TP, which was articulated to the sacrum, and signs of early coronal deformity. She had responded almost completely to repeated steroid injections into the TP-sacral joint, but that effect was very transient. Informed patient consent was obtained prior to her surgery. She underwent a minimally invasive tube disconnection of the abnormal joint with partial distal resection of the TP, and her symptoms completely resolved. This case highlights the importance of correlating clinical symptoms with aberrant anatomy, and the role of selective surgery in providing symptomatic relief. This case report was written in compliance with our institutional ethical review board approval, and patient consent was waived in light of the retrospective and deidentified nature of the data presented in accordance with the University of Texas Southwestern institutional review board.

Trem2 deficiency differentially affects phenotype and transcriptome of human APOE3 and APOE4 mice.

BACKGROUND: Alzheimer's Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOEε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are major genetic risk factors for AD. Recent studies showed that APOE binds to TREM2, thus raising the possibility of an APOE-TREM2 interaction that can modulate AD pathology. METHODS: The aim of this study was to investigate this interaction using complex AD model mice - a crossbreed of Trem2ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms (APP/E3 and APP/E4 respectively), and their WT littermates (E3 and E4), and evaluate cognition, steady-state amyloid load, plaque compaction, plaque growth rate, glial response, and brain transcriptome. RESULTS: In both, APP/E3 and APP/E4 mice, Trem2 deletion reduced plaque compaction but did not significantly affect steady-state plaque load. Importantly, the lack of TREM2 increased plaque growth that negatively correlated to the diminished microglia barrier, an effect most pronounced at earlier stages of amyloid deposition. We also found that Trem2 deficiency significantly decreased plaque-associated APOE protein in APP/E4 but not in APP/E3 mice in agreement with RNA-seq data. Interestingly, we observed a significant decrease of Apoe mRNA expression in plaque-associated microglia of APP/E4/Trem2ko vs APP/E4 mice. The absence of TREM2, worsened cognitive performance in APP transgenic mice but not their WT littermates. Gene expression analysis identified Trem2 signature - a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all genotypes including APP and WT littermates. Furthermore, we identified sets of genes that were affected in TREM2- and APOE isoform-dependent manner. Among them were Clec7a and Csf1r upregulated in APP/E4 vs APP/E3 mice, a result further validated by in situ hybridization analysis. In contrast, Tyrobp and several genes involved in the C1Q complement cascade had a higher expression level in APP/E3 versus their APP/E4 counterparts. CONCLUSIONS: Our data demonstrate that lack of Trem2 differentially impacts the phenotype and brain transcriptome of APP mice expressing human APOE isoforms. The changes probably reflect the different effect of APOE isoforms on amyloid deposition.

Usability of an Immersive Augmented Reality Based Telerehabilitation System with Haptics (ARTESH) for Synchronous Remote Musculoskeletal Examination.

This study describes the features and utility of a novel augmented reality based telemedicine system with haptics that allows the sense of touch and direct physical examination during a synchronous immersive telemedicine consultation and physical examination. The system employs novel engineering features: (a) a new force enhancement algorithm to improve force rendering and overcoming the "just-noticeable-difference" limitation; (b) an improved force compensation method to reduce the delay in force rendering; (c) use of the "haptic interface point" to reduce disparity between the visual and haptic data; and (d) implementation of efficient algorithms to process, compress, decompress, transmit and render 3-D tele-immersion data. A qualitative pilot study (n=20) evaluated the usability of the system. Users rated the system on a 26-question survey using a seven-point Likert scale, with percent agreement calculated from the total users who agreed with a given statement. Survey questions fell into three main categories: (1) ease and simplicity of use, (2) quality of experience, and (3) comparison to in-person evaluation. Average percent agreements between the telemedicine and in-person evaluation were highest for ease and simplicity of use (86%) and quality of experience (85%), followed by comparison to in-person evaluation (58%). Eighty-nine percent (89%) of respondents expressed satisfaction with the overall quality of experience. Results suggest that the system was effective at conveying audio-visual and touch data in real-time across 20.3 miles, and warrants further development.

APOE2 orchestrated differences in transcriptomic and lipidomic profiles of postmortem AD brain.

BACKGROUND: The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer's disease (AD) brain. The results so far have prompted further research using "multi-omics" approaches. These approaches become particularly relevant, considering the inheritance of APOEε4 allele as a major genetic risk factor of AD, disease protective effect of APOEε2 allele, and a major role of APOE in brain lipid metabolism. METHODS: Postmortem brain samples from inferior parietal lobule genotyped as APOEε2/c (APOEε2/carriers), APOEε3/3, and APOEε4/c (APOEε4/carriers), age- and gender-matched, were used to reveal APOE allele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data. RESULTS: Significantly affected GO terms and pathways were determined based on the comparisons of APOEε2/c datasets to those of APOEε3/3 and APOEε4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated in APOEε2/c brain samples compared to both APOEε3/3 and APOEε4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOEε4/c samples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids. CONCLUSIONS: The results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy-canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOEε2/c brains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.

The Role of APOE and TREM2 in Alzheimer's Disease-Current Understanding and Perspectives.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. The extracellular deposits of Amyloid beta (Aß) in the brain-called amyloid plaques, and neurofibrillary tangles-intracellular tau aggregates, are morphological hallmarks of the disease. The risk for AD is a complicated interplay between aging, genetic risk factors, and environmental influences. One of the Apolipoprotein E (APOE) alleles-APOEε4, is the major genetic risk factor for late-onset AD (LOAD). APOE is the primary cholesterol carrier in the brain, and plays an essential role in lipid trafficking, cholesterol homeostasis, and synaptic stability. Recent genome-wide association studies (GWAS) have identified other candidate LOAD risk loci, as well. One of those is the triggering receptor expressed on myeloid cells 2 (TREM2), which, in the brain, is expressed primarily by microglia. While the function of TREM2 is not fully understood, it promotes microglia survival, proliferation, and phagocytosis, making it important for cell viability and normal immune functions in the brain. Emerging evidence from protein binding assays suggests that APOE binds to TREM2 and APOE-containing lipoproteins in the brain as well as periphery, and are putative ligands for TREM2, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner. This review is focusing on the interplay between APOE isoforms and TREM2 in association with AD pathology.

Intraventricular bone dust migration after neuroendoscopy: report of 2 cases.

Neuroendoscopy has demonstrated safety and efficacy in the treatment of a host of pediatric neurosurgical pathologies. With the increase in its applicability, several associated complications have been described in the literature. A common practice in pediatric neurosurgery is the use of Gelfoam sponge pledget in the burr hole, followed by bone fragments and dust (obtained from the created burr hole), to cover the dural defect. This technique is used to enhance burr hole sealing and potentially prevent CSF leakage from the surgical site. Reports on intracranial bone dust migration associated with this technique are scarce. The authors report 2 cases of intracranial migration of bone fragments after an endoscopic third ventriculostomy and an endoscopic colloid cyst resection. The bone fragment migration was thought to be caused by negative pressure from a lumbar puncture in one case and external trauma to the head in the other. As endoscopy becomes more widely used, it is important to be aware of this potential complication that may in some cases require an intervention. A review of the cases reported in the literature is provided and a technique is suggested to help prevent this complication.

Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots: A Case Report and Review of the Literature.

BACKGROUND: Juvenile xanthogranuloma (JXG) is a rare, non-Langerhans cell histiocytic disorder that primarily presents as multiple cutaneous lesions in young males. Solitary lesions in the spinal column are an especially rare presentation of this disease, and central nervous system involvement can portend a poor prognosis. We report an unusual case of an adult woman with an unresectable JXG of the lumbar spine. A review of the reported cases of thoracolumbar JXG and the current data regarding diagnosis and treatment are presented. CASE DESCRIPTION: A 28-year-old woman presented with back pain and worsening lower extremity pain, numbness, and weakness. Magnetic resonance imaging demonstrated an enhancing lumbar mass. However, at surgery, no discrete mass was identified. Multiple roots were grossly enlarged, and electrical stimulation identified the L4 root with the most abnormal findings. Despite an attempt at debulking, most of the mass could not be safely removed. The patient experienced incomplete improvement of the symptoms postoperatively but elected to forgo chemotherapy. The 3-month follow-up imaging study showed active lumbar spinal disease, and imaging and follow-up examinations at 27 months revealed no changes. Her symptoms were satisfactorily controlled with conservative therapy. CONCLUSIONS: JXG of the spine is a rare disease with nonspecific clinical and radiographic findings that can make it difficult to diagnose and dictates the use of immunohistochemical staining. If possible, total surgical resection will offer the best outcomes; however, other modalities such as chemotherapy can be viable alternatives or adjuvant modalities.

ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms.

Expression of human Apolipoprotein E (APOE) modulates the inflammatory response in an isoform specific manner, with APOE4 isoform eliciting a stronger pro-inflammatory response, suggesting a possible mechanism for worse outcome following traumatic brain injury (TBI). APOE lipidation and stability is modulated by ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein that transports lipids and cholesterol onto APOE. We examined the impact of Abca1 deficiency and APOE isoform expression on the response to TBI using 3-months-old, human APOE3+/+ (E3/Abca1+/+) and APOE4+/+ (E4/Abca1+/+) targeted replacement mice, and APOE3+/+ and APOE4+/+ mice with only one functional copy of the Abca1 gene (E3/Abca1+/-; E4/Abca1+/-). TBI-treated mice received a craniotomy followed by a controlled cortical impact (CCI) brain injury in the left hemisphere; sham-treated mice received the same surgical procedure without the impact. We performed RNA-seq using samples from cortices and hippocampi followed by genome-wide differential gene expression analysis. We found that TBI significantly impacted unique transcripts within each group, however, the proportion of unique transcripts was highest in E4/Abca1+/- mice. Additionally, we found that Abca1 haplodeficiency increased the expression of microglia sensome genes among only APOE4 injured mice, a response not seen in injured APOE3 mice, nor in either group of sham-treated mice. To identify gene networks, or modules, correlated to TBI, APOE isoform and Abca1 haplodeficiency, we used weighted gene co-expression network analysis (WGCNA). The module that positively correlated to TBI groups was associated with immune response and featured hub genes that were microglia-specific, including Trem2, Tyrobp, Cd68 and Hexb. The modules positively correlated with APOE4 isoform and negatively to Abca1 haplodeficient mice represented "protein translation" and "oxidation-reduction process", respectively. Our results reveal E4/Abca1+/- TBI mice have a distinct response to injury, and unique gene networks are associated with APOE isoform, Abca1 insufficiency and injury.

Heavy Chronic Intermittent Ethanol Exposure Alters Small Noncoding RNAs in Mouse Sperm and Epididymosomes.

While the risks of maternal alcohol abuse during pregnancy are well-established, several preclinical studies suggest that chronic preconception alcohol consumption by either parent may also have significance consequences for offspring health and development. Notably, since isogenic male mice used in these studies are not involved in gestation or rearing of offspring, the cross-generational effects of paternal alcohol exposure suggest a germline-based epigenetic mechanism. Many recent studies have demonstrated that the effects of paternal environmental exposures such as stress or malnutrition can be transmitted to the next generation via alterations to small noncoding RNAs in sperm. Therefore, we used high throughput sequencing to examine the effect of preconception ethanol on small noncoding RNAs in sperm. We found that chronic intermittent ethanol exposure altered several small noncoding RNAs from three of the major small RNA classes in sperm, tRNA-derived small RNA (tDR), mitochondrial small RNA, and microRNA. Six of the ethanol-responsive small noncoding RNAs were evaluated with RT-qPCR on a separate cohort of mice and five of the six were confirmed to be altered by chronic ethanol exposure, supporting the validity of the sequencing results. In addition to altered sperm RNA abundance, chronic ethanol exposure affected post-transcriptional modifications to sperm small noncoding RNAs, increasing two nucleoside modifications previously identified in mitochondrial tRNA. Furthermore, we found that chronic ethanol reduced epididymal expression of a tRNA methyltransferase, Nsun2, known to directly regulate tDR biogenesis. Finally, ethanol-responsive sperm tDR are similarly altered in extracellular vesicles of the epididymis (i.e., epididymosomes), supporting the hypothesis that alterations to sperm tDR emerge in the epididymis and that epididymosomes are the primary source of small noncoding RNAs in sperm. These results add chronic ethanol to the growing list of paternal exposures that can affect small noncoding RNA abundance and nucleoside modifications in sperm. As small noncoding RNAs in sperm have been shown to causally induce heritable phenotypes in offspring, additional research is warranted to understand the potential effects of ethanol-responsive sperm small noncoding RNAs on offspring health and development.

Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice. To identify differentially expressed genes and gene-networks correlated to diet, APOE isoform and sex, we performed RNA sequencing and applied Weighted Gene Co-expression Network Analysis. We determined that the immune response network with major hubs Tyrobp/DAP12, Csf1r, Tlr2, C1qc and Laptm5 correlated significantly and positively to the phenotype of female APP/E4-HFD mice. Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage around plaques, particularly of larger size, was significantly reduced. This suggests altered containment of the plaque growth and sex-dependent vulnerability in response to diet. The results of our study show concurrent impact of diet, APOE isoform and sex on the brain transcriptome and AD-like phenotype.

Effect of high fat diet on phenotype, brain transcriptome and lipidome in Alzheimer's model mice.

We examined the effect of chronic high fat diet (HFD) on amyloid deposition and cognition of 12-months old APP23 mice, and correlated the phenotype to brain transcriptome and lipidome. HFD significantly increased amyloid plaques and worsened cognitive performance compared to mice on normal diet (ND). RNA-seq results revealed that in HFD mice there was an increased expression of genes related to immune response, such as Trem2 and Tyrobp. We found a significant increase of TREM2 immunoreactivity in the cortex in response to HFD, most pronounced in female mice that correlated to the amyloid pathology. Down-regulated by HFD were genes related to neuron projections and synaptic transmission in agreement to the significantly deteriorated neurite morphology and cognition in these mice. To examine the effect of the diet on the brain lipidome, we performed Shotgun Lipidomics. While there was no difference in the total amounts of phospholipids of each class, we revealed that the levels of 24 lipid sub-species in the brain were significantly modulated by HFD. Network visualization of correlated lipids demonstrated overall imbalance with most prominent effect on cardiolipin molecular sub-species. This integrative approach demonstrates that HFD elicits a complex response at molecular, cellular and system levels in the CNS.

Gene co-expression networks identify Trem2 and Tyrobp as major hubs in human APOE expressing mice following traumatic brain injury.

Traumatic brain injury (TBI) is strongly linked to an increased risk of developing dementia, including chronic traumatic encephalopathy and possibly Alzheimer's disease (AD). APOEε4 allele of human Apolipoprotein E (APOE) gene is the major genetic risk factor for late onset AD and has been associated with chronic traumatic encephalopathy and unfavorable outcome following TBI. To determine if there is an APOE isoform-specific response to TBI we performed controlled cortical impact on 3-month-old mice expressing human APOE3 or APOE4 isoforms. Following injury, we used several behavior paradigms to test for anxiety and learning and found that APOE3 and APOE4 targeted replacement mice demonstrate cognitive impairments following moderate TBI. Transcriptional profiling 14days following injury revealed a significant effect of TBI, which was similar in both genotypes. Significantly upregulated by injury in both genotypes were mRNA expression and protein level of ABCA1 transporter and APOJ, but not APOE. To identify gene-networks correlated to injury and APOE isoform, we performed Weighted Gene Co-expression Network Analysis. We determined that the network mostly correlated to TBI in animals expressing both isoforms is immune response with major hub genes including Trem2, Tyrobp, Clec7a and Cd68. We also found a significant increase of TREM2, IBA-1 and GFAP protein levels in the brains of injured mice. We identified a network representing myelination that correlated significantly with APOE isoform in both injury groups. This network was significantly enriched in oligodendrocyte signature genes, such as Mbp and Plp1. Our results demonstrate unique and distinct gene networks at this acute time point for injury and APOE isoform, as well as a network driven by APOE isoform across TBI groups.

Liver X receptor agonist treatment significantly affects phenotype and transcriptome of APOE3 and APOE4 Abca1 haplo-deficient mice.

ATP-binding cassette transporter A1 (ABCA1) controls cholesterol and phospholipid efflux to lipid-poor apolipoprotein E (APOE) and is transcriptionally controlled by Liver X receptors (LXRs) and Retinoic X Receptors (RXRs). In APP transgenic mice, lack of Abca1 increased Aß deposition and cognitive deficits. Abca1 haplo-deficiency in mice expressing human APOE isoforms, increased level of Aß oligomers and worsened memory deficits, preferentially in APOE4 mice. In contrast upregulation of Abca1 by LXR/RXR agonists significantly ameliorated pathological phenotype of those mice. The goal of this study was to examine the effect of LXR agonist T0901317 (T0) on the phenotype and brain transcriptome of APP/E3 and APP/E4 Abca1 haplo-deficient (APP/E3/Abca1+/- and APP/E4/Abca1+/-) mice. Our data demonstrate that activated LXRs/RXR ameliorated APOE4-driven pathological phenotype and significantly affected brain transcriptome. We show that in mice expressing either APOE isoform, T0 treatment increased mRNA level of genes known to affect brain APOE lipidation such as Abca1 and Abcg1. In both APP/E3/Abca1+/- and APP/E4/Abca1+/- mice, the application of LXR agonist significantly increased ABCA1 protein level accompanied by an increased APOE lipidation, and was associated with restoration of APOE4 cognitive deficits, reduced levels of Aß oligomers, but unchanged amyloid load. Finally, using Gene set enrichment analysis we show a significant APOE isoform specific response to LXR agonist treatment: Gene Ontology categories "Microtubule Based Process" and "Synapse Organization" were differentially affected in T0-treated APP/E4/Abca1+/- mice. Altogether, the results are suggesting that treatment of APP/E4/Abca1+/- mice with LXR agonist T0 ameliorates APOE4-induced AD-like pathology and therefore targeting the LXR-ABCA1-APOE regulatory axis could be effective as a potential therapeutic approach in AD patients, carriers of APOEε4.