Sulfonamide disinfection byproducts exhibited severe toxicity to human commensal bacteria.

Many antibiotic disinfection byproducts have been detected but their toxicity has not been evaluated adequately. In this report, the chlorination reaction kinetics of five common sulfamides (SAs), reaction intermediates and their toxicity were investigated. Chlorination of sulfapyridine (SPD), sulfamethazine (SMT), sulfathiazole (STZ), and sulfisoxazole (SIZ) followed the second-order kinetics, and were degraded completely within 10 min. A large number of reaction intermediates were deteced by LC-MS, among which a total of 16 intermediates were detected for the first time. Toxicity of the five SAs chlorination solutions was evaluated separately by examining their effects on the growth rate of S. salivarius K12, a commensal bacterium in the human digestive system. After 30 min chlorination, solutions of SMT, STZ and sulfadiazine (SDZ) each exhibited severe toxicity by inhibiting the bacteria growth completely, whereas the inhibition was only 50 % and 20  % by SIZ and SPD respectively. Based on the comparison between toxicity test results and mass spectra, three SA chlorination intermediates, m/z 187.2 (C10H10N4), m/z 287.2 (C9H7N3O4S2) and m/z 215 (C7H10N4O2S/C12H14N4) were proposed to be the primary toxicants in the chlorination products. Our study demonstrated the power of combined approach of chemical analysis and toxicity testing in identifying toxic disinfection byproducts, and highlighted the ne ed for more research on the toxicity evaluation and risk assessment of antibiotic disinfection byproducts.

Updates on mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial AD (FAD) patients. Newer generations of mouse models through knock-in (KI)/knock-out (KO) or CRISPR gene editing technologies, have been developed for both familial and sporadic AD risk genes with the hope to more accurately model proteinopathies without over-expression of human AD genes in mouse brains. In this review, we summarized the phenotypes of a few commonly used as well as newly developed mouse models in translational research laboratories including the presence or absence of key pathological features of AD such as amyloid and tau pathology, synaptic and neuronal degeneration as well as cognitive and behavior deficits. In addition, advantages and limitations of these AD mouse models have been elaborated along with discussions of any sex-specific features. More importantly, the omics data from available AD mouse models have been analyzed to categorize molecular signatures of each model reminiscent of human AD brain changes, with the hope to guide future selection of most suitable models for specific research questions to be addressed in the AD field.

APOE2 Heterozygosity Reduces Hippocampal Soluble Amyloid-ß42 Levels in Non-Hyperlipidemic Mice.

APOE2 lowers Alzheimer's disease (AD) risk; unfortunately, the mechanism remains poorly understood and the use of mice models is problematic as APOE2 homozygosity is associated with hyperlipidemia. In this study, we developed mice that are heterozygous for APOE2 and APOE3 or APOE4 and overexpress amyloid-ß peptide (Aß) (EFAD) to evaluate the effect of APOE2 dosage on Aß pathology. We found that heterozygous mice do not exhibit hyperlipidemia. Hippocampal but not cortical levels of soluble Aß42 followed the order E2/2FAD > E2/3FAD≤E3/3FAD and E2/2FAD > E2/4FAD < E4/4FAD without an effect on insoluble Aß42. These findings offer initial insights on the impact of APOE2 on Aß pathology.

Binder-Free MOF-Based and MOF-Derived Nanoarrays for Flexible Electrochemical Energy Storage: Progress and Perspectives.

The fast development of Internet of Things and the rapid advent of next-generation versatile wearable electronics require cost-effective and highly-efficient electroactive materials for flexible electrochemical energy storage devices. Among various electroactive materials, binder-free nanostructured arrays have attracted widespread attention. Featured with growing on a conductive and flexible substrate without using inactive and insulating binders, binder-free 3D nanoarray electrodes facilitate fast electron/ion transportation and rapid reaction kinetics with more exposed active sites, maintain structure integrity of electrodes even under bending or twisted conditions, readily release generated joule heat during charge/discharge cycles and achieve enhanced gravimetric capacity of the whole device. Binder-free metal-organic framework (MOF) nanoarrays and/or MOF-derived nanoarrays with high surface area and unique porous structure have emerged with great potential in energy storage field and been extensively exploited in recent years. In this review, common substrates used for binder-free nanoarrays are compared and discussed. Various MOF-based and MOF-derived nanoarrays, including metal oxides, sulfides, selenides, nitrides, phosphides and nitrogen-doped carbons, are surveyed and their electrochemical performance along with their applications in flexible energy storage are analyzed and overviewed. In addition, key technical issues and outlooks on future development of MOF-based and MOF-derived nanoarrays toward flexible energy storage are also offered.

Blood-based biomarkers in Alzheimer's disease: Future directions for implementation.

INTRODUCTION: Disease-modifying therapies (DMTs) for Alzheimer's disease (AD) will increase diagnostic demand. A non-invasive blood-based biomarker (BBBM) test for detection of amyloid-ß pathology may reduce diagnostic barriers and facilitate DMT initiation. OBJECTIVE: To explore heterogeneity in AD care pathways and potential role of BBBM tests. METHODS: Survey of 213 healthcare professionals/payers in US/China/UK/Germany/Spain/France and two advisory boards (US/Europe). RESULTS: Current diagnostic pathways are heterogeneous, meaning many AD patients are missed while low-risk patients undergo unnecessary procedures. Confirmatory amyloid testing (cerebrospinal fluid biomarkers/positron emission tomography) is utilized in few patients, resulting in diagnostic/treatment delays. A high negative-predictive-value test could streamline the diagnostic pathway by reducing unnecessary procedures in low-risk patients; supporting confirmatory testing where needed. Imminent approval of DMTs will increase need for fast and reliable AD diagnostic tests. DISCUSSION: An easy-to-use, accurate, non-invasive BBBM test for amyloid pathology could guide diagnostic procedures or referral, streamlining early diagnosis and DMT initiation. Highlights: This study explored AD care pathways and how BBBM may meet diagnostic demandsCurrent diagnostic pathways are heterogeneous, with country and setting variationsMany AD patients are missed, while low-risk patients undergo unnecessary proceduresAn easy-to-use, accurate, non-invasive BBBM test for amyloid pathology is neededThis test could streamline early diagnosis of amyloid pathology and DMT initiation.

Multi-omic atlas of the parahippocampal gyrus in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia worldwide, with a projection of 151 million cases by 2050. Previous genetic studies have identified three main genes associated with early-onset familial Alzheimer's disease, however this subtype accounts for less than 5% of total cases. Next-generation sequencing has been well established and holds great promise to assist in the development of novel therapeutics as well as biomarkers to prevent or slow the progression of this devastating disease. Here we present a public resource of functional genomic data from the parahippocampal gyrus of 201 postmortem control, mild cognitively impaired (MCI) and AD individuals from the Mount Sinai brain bank, of which whole-genome sequencing (WGS), and bulk RNA sequencing (RNA-seq) were previously published. The genomic data include bulk proteomics and DNA methylation, as well as cell-type-specific RNA-seq and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) data. We have performed extensive preprocessing and quality control, allowing the research community to access and utilize this public resource available on the Synapse platform at https://doi.org/10.7303/syn51180043.2 .

Synaptojanin 1 Modulates Functional Recovery After Incomplete Spinal Cord Injury in Male Apolipoprotein E Epsilon 4 Mice.

Apolipoprotein E epsilon 4 (ApoE4) is the second most common variant of ApoE, being present in ∼14% of the population. Clinical reports identify ApoE4 as a genetic risk factor for poor outcomes after traumatic spinal cord injury (SCI) and spinal cord diseases such as cervical myelopathy. To date, there is no intervention to promote recovery of function after SCI/spinal cord diseases that is specifically targeted at ApoE4-associated impairment. Studies in the human and mouse brain link ApoE4 to elevated levels of synaptojanin 1 (synj1), a lipid phosphatase that degrades phosphoinositol 4,5-bisphosphate (PIP2) into inositol 4-monophosphate. Synj1 regulates rearrangements of the cytoskeleton as well as endocytosis and trafficking of synaptic vesicles. We report here that, as compared to ApoE3 mice, levels of synj1 messenger RNA and protein were elevated in spinal cords of healthy ApoE4 mice associated with lower PIP2 levels. Using a moderate-severity model of contusion SCI in mice, we found that genetic reduction of synj1 improved locomotor function recovery at 14 days after SCI in ApoE4 mice without altering spared white matter. Genetic reduction of synj1 did not alter locomotor recovery of ApoE3 mice after SCI. Bulk RNA sequencing revealed that at 14 days after SCI in ApoE4 mice, genetic reduction of synj1 upregulated genes involved in glutaminergic synaptic transmission just above and below the lesion. Overall, our findings provide evidence for a link between synj1 to poor outcomes after SCI in ApoE4 mice, up to 14 days post-injury, through mechanisms that may involve the function of excitatory glutaminergic neurons.

Molecular differences in brain regional vulnerability to aging between males and females.

Background: Aging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive. Results: Using the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer's disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases. Conclusions: This integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD.

Sex specific molecular networks and key drivers of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive and age-associated neurodegenerative disorder that affects women disproportionally. However, the underlying mechanisms are poorly characterized. Moreover, while the interplay between sex and ApoE genotype in AD has been investigated, multi-omics studies to understand this interaction are limited. Therefore, we applied systems biology approaches to investigate sex-specific molecular networks of AD. METHODS: We integrated large-scale human postmortem brain transcriptomic data of AD from two cohorts (MSBB and ROSMAP) via multiscale network analysis and identified key drivers with sexually dimorphic expression patterns and/or different responses to APOE genotypes between sexes. The expression patterns and functional relevance of the top sex-specific network driver of AD were further investigated using postmortem human brain samples and gene perturbation experiments in AD mouse models. RESULTS: Gene expression changes in AD versus control were identified for each sex. Gene co-expression networks were constructed for each sex to identify AD-associated co-expressed gene modules shared by males and females or specific to each sex. Key network regulators were further identified as potential drivers of sex differences in AD development. LRP10 was identified as a top driver of the sex differences in AD pathogenesis and manifestation. Changes of LRP10 expression at the mRNA and protein levels were further validated in human AD brain samples. Gene perturbation experiments in EFAD mouse models demonstrated that LRP10 differentially affected cognitive function and AD pathology in sex- and APOE genotype-specific manners. A comprehensive mapping of brain cells in LRP10 over-expressed (OE) female E4FAD mice suggested neurons and microglia as the most affected cell populations. The female-specific targets of LRP10 identified from the single cell RNA-sequencing (scRNA-seq) data of the LRP10 OE E4FAD mouse brains were significantly enriched in the LRP10-centered subnetworks in female AD subjects, validating LRP10 as a key network regulator of AD in females. Eight LRP10 binding partners were identified by the yeast two-hybrid system screening, and LRP10 over-expression reduced the association of LRP10 with one binding partner CD34. CONCLUSIONS: These findings provide insights into key mechanisms mediating sex differences in AD pathogenesis and will facilitate the development of sex- and APOE genotype-specific therapies for AD.

The utility of word list and story recall for identifying older U.S. Chinese immigrants with cognitive impairment.

OBJECTIVE: This study examined the utility of the Chinese-language translations of the word list memory test (Philadelphia Verbal Learning Test) and story memory test (Logical Memory subtest of the Wechsler Memory Scale) for differentiating cognitive diagnosis in older U.S. Chinese immigrants. METHOD: Participants were ≥ 60 years old, with Chinese language proficiency to complete a diagnostic workup at the Mount Sinai's Alzheimer's Disease Research Center. The workup included an evaluation by a geriatric psychiatrist and cognitive testing with a psychometrician. Diagnosis of normal, mild cognitive impairment (MCI), and dementia was made independent of the cognitive tests at consensus led by a dementia expert physician. Multivariable logistic regression models were used to assess the sensitivity of story and word list memory tests for distinguishing between groups. Receiver operating characteristic (ROC area/area under the curve [AUC]) was used to compare the predictive accuracy of the two tests. RESULTS: The sample included 71 participants with normal cognition, 42 with MCI, and 24 with dementia. The MCI group was older and less educated than normal controls but younger and more educated than the dementia group. Delayed recall of both memory tests, but not immediate recall of either test, predicted diagnosis. While composite memory score of word list (AUC = 0.90) predicted diagnosis slightly better than that of stories (AUC = 0.85), the difference was not significant in this small sample (p = .14). CONCLUSIONS: Chinese-language translations of verbal memory tests, in particular delayed recall scores, were equally sensitive for classifying cognitive diagnosis in older U.S. Chinese immigrants. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The use of subjective cognitive complaints for detecting mild cognitive impairment in older adults across cultural and linguistic groups: A comparison of the Cognitive Function Instrument to the Montreal Cognitive Assessment.

INTRODUCTION: This pilot study aims to explore the psychometric properties of the Cognitive Function Instrument (CFI) as a measure of subjective cognitive complaints (SCC) and its performance in distinguishing mild cognitive impairment (MCI) from normal control (NC) compared to an objective cognitive screen (Montreal Cognitive Assessment [MoCA]). METHODS: One hundred ninety-four community-dwelling non-demented older adults with racial/ethnic diversity were included. Unidimensionality and internal consistency of the CFI were examined using factor analysis, Cronbach's alpha, and McDonald's omega. Logistic regression models and receiver operating characteristic (ROC) analysis were used to examine the performance of CFI. RESULTS: The CFI demonstrated adequate internal consistency; however, the fit for a unidimensional model was suboptimal. The CFI distinguished MCI from NC alone or in combination with MoCA. ROC analysis showed comparable performance of the CFI and the MoCA. DISCUSSION: Our findings support the use of CFI as a brief and easy-to-use screen to detect MCI in culturally/linguistically diverse older adults. HIGHLIGHT: What is the key scientific question or problem of central interest of the paper? Subjective cognitive complaints (SCCs) are considered the earliest sign of dementia in older adults. However, it is unclear if SCC are equivalent in different cultures. The Cognitive Function Instrument (CFI) is a 14-item measure of SCC. This study provides pilot data suggesting that CFI is sensitive for detecting mild cognitive impairment in a cohort of older adults with racial/ethnic diversity. Comparing performance, CFI demonstrates comparable sensitivity to the Montreal Cognitive Assessment, an objective cognitive screening test. Overall, SCC may provide a non-invasive, easy-to-use method to flag possible cognitive impairment in both research and clinical settings.

Non-coding RNAs in Alzheimer's disease: perspectives from omics studies.

Neurodegenerative diseases such as Alzheimer's disease (AD) are characterized by the progressive loss of neurons in the brain and the spinal cord. The pathophysiology of AD is multifactorial with heterogeneous molecular manifestations. The lack of efficacious therapies for AD reinforces the importance of exploring in depth multifaceted disease mechanisms. Recent progresses on AD have generated a large amount of RNA-sequencing data at both bulk and single cell levels and revealed thousands of genes with expression changes in AD. However, the upstream regulators of such gene expression changes are largely unknown. Non-coding RNAs (ncRNAs) represent the majority of the human transcriptome, and regulatory ncRNAs have been found to play an important role in regulating gene expression. A single miRNA usually targets a number of mRNAs and thus such ncRNAs are particular important for understanding disease mechanisms and developing novel therapeutics. This review aims to summarize the recent findings on the roles of ncRNAs in AD from ncRNA-omics studies with a focus on ncRNA signatures, interactions between ncRNAs and mRNAs, and ncRNA-regulated pathways in AD. We also review the potential of specific ncRNAs to serve as biomarkers and therapeutic targets for AD. In the end, we point out future directions for studying ncRNAs in AD.

APOE4 confers transcriptomic and functional alterations to primary mouse microglia.

Common genetic variants in more than forty loci modulate risk for Alzheimer's disease (AD). AD risk alleles are enriched within enhancers active in myeloid cells, suggesting that microglia, the brain-resident macrophages, may play a key role in the etiology of AD. A major genetic risk factor for AD is Apolipoprotein E (APOE) genotype, with the ε4/ε4 (E4) genotype increasing risk for AD by approximately 15 fold compared to the most common ε3/ε3 (E3) genotype. However, the impact of APOE genotype on microglial function has not been thoroughly investigated. To address this, we cultured primary microglia from mice in which both alleles of the mouse Apoe gene have been humanized to encode either human APOE ε3 or APOE ε4. Relative to E3 microglia, E4 microglia exhibit altered morphology, increased endolysosomal mass, increased cytokine/chemokine production, and increased lipid and lipid droplet accumulation at baseline. These changes were accompanied by decreased translation and increased phosphorylation of eIF2ɑ and eIF2ɑ-kinases that participate in the integrated stress response, suggesting that E4 genotype leads to elevated levels of cellular stress in microglia relative to E3 genotype. Using live-cell imaging and flow cytometry, we also show that E4 microglia exhibited increased phagocytic uptake of myelin and other substrates compared to E3 microglia. While transcriptomic profiling of myelin-challenged microglia revealed a largely overlapping response profile across genotypes, differential enrichment of genes in interferon signaling, extracellular matrix and translation-related pathways was identified in E4 versus E3 microglia both at baseline and following myelin challenge. Together, our results suggest E4 genotype confers several important functional alterations to microglia even prior to myelin challenge, providing insight into the molecular and cellular mechanisms by which APOE4 may increase risk for AD.

The 32-Item Multilingual Naming Test: Cultural and Linguistic Biases in Monolingual Chinese-Speaking Older Adults.

OBJECTIVES: This study describes the performance of the Multilingual Naming Test (MINT) by Chinese American older adults who are monolingual Chinese speakers. An attempt was also made to identify items that could introduce bias and warrant attention in future investigation. METHODS: The MINT was administered to 67 monolingual Chinese older adults as part of the standard dementia evaluation at the Alzheimer's Disease Research Center (ADRC) at the Icahn School of Medicine at Mount Sinai (ISMMS), New York, USA. A diagnosis of normal cognition (n = 38), mild cognitive impairment (n = 12), and dementia (n = 17) was assigned to all participants at clinical consensus conferences using criterion sheets developed at the ADRC at ISMMS. RESULTS: MINT scores were negatively correlated with age and positively correlated with education, showing sensitivity to demographic factors. One item, butterfly, showed no variations in responses across diagnostic groups. Inclusion of responses from different regions of China changed the answers from "incorrect" to "correct" on 20 items. The last five items, porthole, anvil, mortar, pestle, and axle, yielded a high nonresponse rate, with more than 70% of participants responding with "I don't know." Four items, funnel, witch, seesaw, and wig, were not ordered with respect to item difficulty in the Chinese language. Two items, gauge and witch, were identified as culturally biased for the monolingual group. CONCLUSIONS: Our study highlights the cultural and linguistic differences that might influence the test performance. Future studies are needed to revise the MINT using more universally recognized items of similar word frequency across different cultural and linguistic groups.

Sex Differences in Alzheimer's Disease: Insights From the Multiomics Landscape.

Alzheimer's disease (AD) has complex etiologies, and the impact of sex on AD varies over the course of disease development. The literature provides some evidence of sex-specific contributions to AD. However, molecular mechanisms of sex-biased differences in AD remain elusive. Multiomics data in tandem with systems biology approaches offer a new avenue to dissect sex-stratified molecular mechanisms of AD and to develop sex-specific diagnostic and therapeutic strategies for AD. Single-cell transcriptomic datasets and cell deconvolution of bulk tissue transcriptomic data provide additional insights into brain cell type-specific impact on sex-biased differences in AD. In this review, we summarize the impact of sex chromosomes and sex hormones on AD, the impact of sex-biased differences during AD development, and the interplay between sex and a major AD genetic risk factor, the APOE ε4 genotype, through the multiomics landscape. Several sex-biased molecular pathways such as neuroinflammation and bioenergetic metabolism have been identified. The importance of sex chromosome and sex hormones, as well as the associated pathways in AD pathogenesis, is further strengthened by findings from omics studies. Future research efforts should integrate the multiomics data from different brain regions and different cell types using systems biology approaches, and leverage the knowledge into a holistic examination of sex differences in AD. Advances in systems biology technologies and increasingly available large-scale multiomics datasets will facilitate future studies dissecting such complex signaling mechanisms to better understand AD pathogenesis in both sexes, with the ultimate goals of developing efficacious sex- and APOE-stratified preventive and therapeutic interventions for AD.

Smartphone ownership and usage in Chinese- and English-speaking older adults.

BACKGROUND: Data collection by smartphone is becoming more widespread in healthcare research. Previous studies reported racial/ethnical differences in the use of digital health technology. However, cross-language group comparison (Chinese- and English-speaking older adults) were not performed in these studies. This project will expand to smartphone technology use in diverse older populations with a focus on Chinese American older adults who are monolingual Chinese-speakers. METHOD: The Alzheimer's Disease Research Center (ADRC) at Icahn School of Medicine at Mount Sinai (ISMMS) evaluates diverse older populations using National Alzheimer's Coordinating Center's Uniform Data Set (NACC UDS). The UDS has different language versions, including English and Chinese. The evaluation includes a medical examination, cognitive assessments, and a research blood draw. Smartphone ownership and usage were captured using a local questionnaire developed by our ADRC. The questionnaire, available in English and Chinese, was administered by our ADRC coordinators during the COVID-19 pandemic. Multivariate analysis of variance (MANOVA) was used to examine differences in technology ownership and usages between the two language groups, while controlling for age, gender, education, and cognitive status (measured by Clinical Dementia Rating). RESULT: 33 Chinese- and 117 English-speaking older adults who received a diagnosis of normal cognition or mild cognitive impairment at consensus were included in the data analysis. Results reveal a high prevalence of smartphone ownership in our Chinese- (100%) and English-speaking older participants (86.3%). Participants in both language groups use mobile technology for a wide range of purposes, such as getting news and other information (Chinese=90.9%; English=87.2%), sending/receiving text (Chinese=97.0%; English=96.6%), watching videos/TV shows (Chinese=78.8%; English=69.2%), and taking classes (Chinese=57.5%; English=57.3%). However, Chinese-speaking older adults were less likely than English-speaking older adults to use mobile technology to post their own reviews or comments online (Chinese=9.1%; English=39.3%, p=0.001), download or purchase an app (Chinese=21.2%; English=70.9%, p<0.001), track health/ fitness via apps/website (Chinese=12.1%; English=47.9%, p<0.001) and manage/receive medical care (Chinese=15.2%; English=67.5%, p<0.001). CONCLUSION: Our findings highlight potential barriers to smartphone usage in Chinese American older adults with limited English proficiency. The results have implications for how smartphone technology can be used in clinical practice and aging research.

The Human ApoE4 Variant Reduces Functional Recovery and Neuronal Sprouting After Incomplete Spinal Cord Injury in Male Mice.

Spinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two apolipoprotein E (ApoE)4 alleles show worse functional outcomes and longer hospital stays after SCI, but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets.

Alzheimer's disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-ß neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as GABRB2, LRP10, MSN, PLP1, and ATP6V1A We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes. Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease.

MicroRNA-195 rescues ApoE4-induced cognitive deficits and lysosomal defects in Alzheimer's disease pathogenesis.

Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP2) homeostasis to the susceptibility of developing Alzheimer's Disease (AD). In the present study, we have identified miR-195 as a top micro-RNA candidate involved in the ApoE/PIP2 pathway using miRNA profiles in human ROSMAP datasets and mouse microarray studies. Further validation studies have demonstrated that levels of miR-195 are significantly lower in human brain tissue of ApoE4+/- patients with clinical diagnosis of mild cognitive impairment (MCI) or early AD when compared to ApoE4-/- subjects. In addition, brain miR-195 levels are reduced along with disease progression from normal aging to early AD, and cerebrospinal fluid (CSF) miR-195 levels of MCI subjects are positively correlated with cognitive performances as measured by mini-mental status examination (MMSE) and negatively correlated with CSF tau levels, suggesting the involvement of miR-195 in early development of AD with a potential impact on cognition. Similar differences in miR-195 levels are seen in ApoE4+/+ mouse hippocampal brain tissue and cultured neurons when compared to ApoE3+/+ counterparts. Over-expressing miR-195 reduces expression levels of its top predicted target synaptojanin 1 (synj1), a brain PIP2-degrading enzyme. Furthermore, elevating miR-195 ameliorates cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation in ApoE4+/+ mice. In addition, elevating miR-195 rescues AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells of ApoE4+/+ AD subjects while inhibiting miR-195 exacerbates these phenotypes. Together, our data uncover a novel regulatory mechanism of miR-195 targeted at ApoE4-associated brain PIP2 dyshomeostasis, cognitive deficits, and AD pathology.