Publications by authors named "Vahram Haroutunian"

217 Publications

Transcriptional profile of pyramidal neurons in chronic schizophrenia reveals lamina-specific dysfunction of neuronal immunity.

Mol Psychiatry 2021 Jul 16. Epub 2021 Jul 16.

Department of Neurosciences, University of Toledo College of Medicine, Toledo, OH, USA.

While the pathophysiology of schizophrenia has been extensively investigated using homogenized postmortem brain samples, few studies have examined changes in brain samples with techniques that may attribute perturbations to specific cell types. To fill this gap, we performed microarray assays on mRNA isolated from anterior cingulate cortex (ACC) superficial and deep pyramidal neurons from 12 schizophrenia and 12 control subjects using laser-capture microdissection. Among all the annotated genes, we identified 134 significantly increased and 130 decreased genes in superficial pyramidal neurons, while 93 significantly increased and 101 decreased genes were found in deep pyramidal neurons, in schizophrenia compared to control subjects. In these differentially expressed genes, we detected lamina-specific changes of 55 and 31 genes in superficial and deep neurons in schizophrenia, respectively. Gene set enrichment analysis (GSEA) was applied to the entire pre-ranked differential expression gene lists to gain a complete pathway analysis throughout all annotated genes. Our analysis revealed overrepresented groups of gene sets in schizophrenia, particularly in immunity and synapse-related pathways, suggesting the disruption of these pathways plays an important role in schizophrenia. We also detected other pathways previously demonstrated in schizophrenia pathophysiology, including cytokine and chemotaxis, postsynaptic signaling, and glutamatergic synapses. In addition, we observed several novel pathways, including ubiquitin-independent protein catabolic process. Considering the effects of antipsychotic treatment on gene expression, we applied a novel bioinformatics approach to compare our differential expression gene profiles with 51 antipsychotic treatment datasets, demonstrating that our results were not influenced by antipsychotic treatment. Taken together, we found pyramidal neuron-specific changes in neuronal immunity, synaptic dysfunction, and olfactory dysregulation in schizophrenia, providing new insights for the cell-subtype specific pathophysiology of chronic schizophrenia.
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http://dx.doi.org/10.1038/s41380-021-01205-yDOI Listing
July 2021

Erratum to: Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia.

Schizophr Bull 2021 Jun 24. Epub 2021 Jun 24.

Department of Psychiatry, Chaim Sheba Medical Center, Ramat-Gan and the Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

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http://dx.doi.org/10.1093/schbul/sbab073DOI Listing
June 2021

A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex.

Nat Commun 2021 06 10;12(1):3517. Epub 2021 Jun 10.

University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK.

Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).
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http://dx.doi.org/10.1038/s41467-021-23243-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192929PMC
June 2021

Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson's disease and dementia with Lewy bodies.

Acta Neuropathol Commun 2021 04 7;9(1):62. Epub 2021 Apr 7.

Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA.

Definitive diagnosis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding of disease-associated alpha-synuclein (αSyn) as misfolded protein aggregates in the central nervous system (CNS). The recent development of the real-time quaking induced conversion (RT-QuIC) assay for ultrasensitive detection of αSyn aggregates has revitalized the diagnostic values of clinically accessible biospecimens, including cerebrospinal fluid (CSF) and peripheral tissues. However, the current αSyn RT-QuIC assay platforms vary widely and are thus challenging to implement and standardize the measurements of αSyn across a wide range of biospecimens and in different laboratories. We have streamlined αSyn RT-QuIC assay based on a second generation assay platform that was assembled entirely with commercial reagents. The streamlined RT-QuIC method consisted of a simplified protocol requiring minimal hands-on time, and allowing for a uniform analysis of αSyn in different types of biospecimens from PD and DLB. Ultrasensitive and specific RT-QuIC detection of αSyn aggregates was achieved in million-fold diluted brain homogenates and in nanoliters of CSF from PD and DLB cases but not from controls. Comparative analysis revealed higher seeding activity of αSyn in DLB than PD in both brain homogenates and CSF. Our assay was further validated with CSF samples of 214 neuropathologically confirmed cases from tissue repositories (88 PD, 58 DLB, and 68 controls), yielding a sensitivity of 98% and a specificity of 100%. Finally, a single RT-QuIC assay protocol was employed uniformly to detect seeding activity of αSyn in PD samples across different types of tissues including the brain, skin, salivary gland, and colon. We anticipate that our streamlined protocol will enable interested laboratories to easily and rapidly implement the αSyn RT-QuIC assay for various clinical specimens from PD and DLB. The utilization of commercial products for all assay components will improve the robustness and standardization of the RT-QuIC assay for diagnostic applications across different sites. Due to ultralow sample consumption, the ultrasensitive RT-QuIC assay will facilitate efficient use and sharing of scarce resources of biospecimens. Our streamlined RT-QuIC assay is suitable to track the distribution of αSyn in CNS and peripheral tissues of affected patients. The ongoing evaluation of RT-QuIC assay of αSyn as a potential biomarker for PD and DLB in clinically accessible biospecimens has broad implications for understanding disease pathogenesis, improving early and differential diagnosis, and monitoring therapeutic efficacies in clinical trials.
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http://dx.doi.org/10.1186/s40478-021-01175-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028088PMC
April 2021

Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy.

JAMA Neurol 2021 Jun;78(6):736-740

Division of Neuro-Immunology, Department of Neurology, Lenox Hill Hospital, North Shore University Hospital, Zucker School of Medicine at Hofstra/Northwell, New York, New York.

Importance: Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by the JC virus that has no proven effective treatment. Although rare cases of PML have occurred with other anti-CD20 therapies, there had been no prior cases associated with ocrelizumab.

Objective: To report the first ever case of PML occurring with ocrelizumab monotherapy in a patient with progressive multiple sclerosis without prior immunomodulation.

Design, Setting, And Participant: This case was reported from an academic medical center. The patient had multiple sclerosis while receiving ocrelizumab monotherapy.

Exposures: Ocrelizumab monotherapy.

Results: A 78-year-old man with progressive multiple sclerosis treated with ocrelizumab monotherapy for 2 years presented with 2 weeks of progressive visual disturbance and confusion. Examination demonstrated a right homonymous hemianopia, and magnetic resonance imaging revealed an enlarging nonenhancing left parietal lesion without mass effect. Cerebrospinal fluid revealed 1000 copies/mL of JC virus, confirming the diagnosis of PML. Blood work on diagnosis revealed grade 2 lymphopenia, with absolute lymphocyte count of 710/μL, CD4 of 294/μL (reference range, 325-1251/μL), CD8 of 85/μL (reference range, 90-775/μL), CD19 of 1/μL, preserved CD4/CD8 ratio (3.45), and negative HIV serology. Retrospective absolute lymphocyte count revealed intermittent grade 1 lymphopenia that preceded ocrelizumab (absolute lymphocyte count range, 800-1200/μL). The patient's symptoms progressed over weeks to involve bilateral visual loss, right-sided facial droop, and dysphasia. Ocrelizumab was discontinued and off-label pembrolizumab treatment was initiated. The patient nevertheless declined rapidly and ultimately died. PML was confirmed at autopsy.

Conclusions And Relevance: In this case report, PML occurrence was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence. This case report emphasizes the importance of a thorough discussion of the risks and benefits of ocrelizumab, especially in patients at higher risk for infections such as elderly patients.
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http://dx.doi.org/10.1001/jamaneurol.2021.0627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967248PMC
June 2021

Global Profiling of Lysine Accessibility to Evaluate Protein Structure Changes in Alzheimer's Disease.

J Am Soc Mass Spectrom 2021 Apr 8;32(4):936-945. Epub 2021 Mar 8.

Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.

The linear sequence of amino acids in a protein folds into a 3D structure to execute protein activity and function, but it is still challenging to profile the 3D structure at the proteome scale. Here, we present a method of native protein tandem mass tag (TMT) profiling of Lys accessibility and its application to investigate structural alterations in human brain specimens of Alzheimer's disease (AD). In this method, proteins are extracted under a native condition, labeled by TMT reagents, followed by trypsin digestion and peptide analysis using two-dimensional liquid chromatography and tandem mass spectrometry (LC/LC-MS/MS). The method quantifies Lys labeling efficiency to evaluate its accessibility on the protein surface, which may be affected by protein conformations, protein modifications, and/or other molecular interactions. We systematically optimized the amount of TMT reagents, reaction time, and temperature and then analyzed protein samples under multiple conditions, including different labeling time (5 and 30 min), heat treatment, AD and normal human cases. The experiment profiled 15370 TMT-labeled peptides in 4475 proteins. As expected, the heat treatment led to extensive changes in protein conformations, with 17% of the detected proteome displaying differential labeling. Compared to the normal controls, AD brain showed different Lys accessibility of tau and RNA splicing complexes, which are the hallmarks of AD pathology, as well as proteins involved in transcription, mitochondrial, and synaptic functions. To eliminate the possibility that the observed differential Lys labeling was caused by protein level change, the whole proteome was quantified with standard TMT-LC/LC-MS/MS for normalization. Thus, this native protein TMT method enables the proteome-wide measurement of Lys accessibility, representing a straightforward strategy to explore protein structure in any biological system.
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http://dx.doi.org/10.1021/jasms.0c00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255072PMC
April 2021

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

Sci Adv 2021 Jan 6;7(2). Epub 2021 Jan 6.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

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-β neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as , , , , and 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.
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http://dx.doi.org/10.1126/sciadv.abb5398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787497PMC
January 2021

Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy.

J Neuropathol Exp Neurol 2021 01;80(2):102-111

Institute of Neurology, Medical University of Vienna, Vienna, Austria.

Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.
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http://dx.doi.org/10.1093/jnen/nlaa153DOI Listing
January 2021

Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease.

Neuron 2021 01 24;109(2):257-272.e14. Epub 2020 Nov 24.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.
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http://dx.doi.org/10.1016/j.neuron.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855384PMC
January 2021

Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia.

Schizophr Bull 2021 04;47(3):785-795

Department of Psychiatry, Chaim Sheba Medical Center, Ramat-Gan and the Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Background: The main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they have not been identified yet. We performed comprehensive gene expression analysis to search for molecular signals that differentiate schizophrenia patients from healthy controls and examined whether an identified signal was concentrated in a subgroup of the patients.

Methods: Transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI) was performed. Differential expression and pathway enrichment analysis results were compared to an independent cohort. Replicability was tested on 6 additional independent datasets.

Results: The 2 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunit genes in schizophrenia. The signal of proteasome subunits down-regulation was replicated in 6 additional datasets (overall 8 cohorts with 267 schizophrenia and 266 control samples, from 5 brain regions). The signal was concentrated in a subgroup of patients with schizophrenia.

Conclusions: We detected global down-regulation of proteasome subunits in a subgroup of patients with schizophrenia. We hypothesize that the down-regulation of proteasome subunits leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins, which has been recently detected in a subgroup of schizophrenia patients. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.
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http://dx.doi.org/10.1093/schbul/sbaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084431PMC
April 2021

Molecular signature of extracellular matrix pathology in schizophrenia.

Eur J Neurosci 2021 Jun 13;53(12):3960-3987. Epub 2020 Nov 13.

Translational Neuroscience Laboratory, Mclean Hospital, Belmont, MA, USA.

Growing evidence points to a critical involvement of the extracellular matrix (ECM) in the pathophysiology of schizophrenia (SZ). Decreases of perineuronal nets (PNNs) and altered expression of chondroitin sulphate proteoglycans (CSPGs) in glial cells have been identified in several brain regions. GWAS data have identified several SZ vulnerability variants of genes encoding for ECM molecules. Given the potential relevance of ECM functions to the pathophysiology of this disorder, it is necessary to understand the extent of ECM changes across brain regions, their region- and sex-specificity and which ECM components contribute to these changes. We tested the hypothesis that the expression of genes encoding for ECM molecules may be broadly disrupted in SZ across several cortical and subcortical brain regions and include key ECM components as well as factors such as ECM posttranslational modifications and regulator factors. Gene expression profiling of 14 neocortical brain regions, caudate, putamen and hippocampus from control subjects (n = 14/region) and subjects with SZ (n = 16/region) was conducted using Affymetrix microarray analysis. Analysis across brain regions revealed widespread dysregulation of ECM gene expression in cortical and subcortical brain regions in SZ, impacting several ECM functional key components. SRGN, CD44, ADAMTS1, ADAM10, BCAN, NCAN and SEMA4G showed some of the most robust changes. Region-, sex- and age-specific gene expression patterns and correlation with cognitive scores were also detected. Taken together, these findings contribute to emerging evidence for large-scale ECM dysregulation in SZ and point to molecular pathways involved in PNN decreases, glial cell dysfunction and cognitive impairment in SZ.
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http://dx.doi.org/10.1111/ejn.15009DOI Listing
June 2021

Role of cumulative biological risk in mediating socioeconomic disparities in cognitive function in the elderly: a mediation analysis.

BMJ Open 2020 09 18;10(9):e035847. Epub 2020 Sep 18.

Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Objectives: To evaluate whether allostatic load (AL), a measure of cumulative biological risk, fully or partially mediates observed socioeconomic status (SES) differences in cognitive function in the elderly.

Design: Cross-sectional mediation analysis.

Setting: Community-dwelling US elderly who participated in the National Health and Nutrition Examination Survey (NHANES).

Participants: The NHANES uses a complex, multistage, probability sampling design to select a nationally representative sample. Of the 4976 elderly (60 years or older) who were selected, 3234 agreed to participate in the household and medical exam interviews (65% response rate).

Primary And Secondary Outcome Measures: Performance on the Digit Symbol Substitution Test (DSST)-a measure of cognitive function.

Results: Relative to participants with the lowest level of education or family income, participants who were college graduates (β=24.4, 95% CI 22 to 26.8, p<0.0001) or in the highest income quartile (β=17.3, 95% CI 15.2 to 19.4, p<0.0001) had the highest DSST scores and the least AL burden (β=-0.72, 95% CI -0.98 to -0.47 and β=-0.82, 95% CI -1 to -0.57; p<0.0001, respectively). Although, AL was significantly negatively associated with cognitive performance (β = -1, 95% CI -1.4 to -0.5, p<0.0001), it mediated at most 4.5% of the SES effect on DSST performance.

Conclusions: The findings suggest that AL, as measured by a summary index of parameters for cardiovascular function, metabolism and chronic inflammation, is not a significant mediator of SES-related differences in cognitive function in the elderly. Further efforts are required to elucidate the exact physiological pathways and mechanisms through which SES impacts cognitive function in late life.
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http://dx.doi.org/10.1136/bmjopen-2019-035847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511641PMC
September 2020

Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease.

Nat Commun 2020 08 7;11(1):3942. Epub 2020 Aug 7.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene- and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.
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http://dx.doi.org/10.1038/s41467-020-17405-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414858PMC
August 2020

Integrated analysis of ultra-deep proteomes in cortex, cerebrospinal fluid and serum reveals a mitochondrial signature in Alzheimer's disease.

Mol Neurodegener 2020 07 25;15(1):43. Epub 2020 Jul 25.

Departments of Structural Biology and Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Background: Based on amyloid cascade and tau hypotheses, protein biomarkers of different Aβ and tau species in cerebrospinal fluid (CSF) and blood/plasma/serum have been examined to correlate with brain pathology. Recently, unbiased proteomic profiling of these human samples has been initiated to identify a large number of novel AD biomarker candidates, but it is challenging to define reliable candidates for subsequent large-scale validation.

Methods: We present a comprehensive strategy to identify biomarker candidates of high confidence by integrating multiple proteomes in AD, including cortex, CSF and serum. The proteomes were analyzed by the multiplexed tandem-mass-tag (TMT) method, extensive liquid chromatography (LC) fractionation and high-resolution tandem mass spectrometry (MS/MS) for ultra-deep coverage. A systems biology approach was used to prioritize the most promising AD signature proteins from all proteomic datasets. Finally, candidate biomarkers identified by the MS discovery were validated by the enzyme-linked immunosorbent (ELISA) and TOMAHAQ targeted MS assays.

Results: We quantified 13,833, 5941, and 4826 proteins from human cortex, CSF and serum, respectively. Compared to other studies, we analyzed a total of 10 proteomic datasets, covering 17,541 proteins (13,216 genes) in 365 AD, mild cognitive impairment (MCI) and control cases. Our ultra-deep CSF profiling of 20 cases uncovered the majority of previously reported AD biomarker candidates, most of which, however, displayed no statistical significance except SMOC1 and TGFB2. Interestingly, the AD CSF showed evident decrease of a large number of mitochondria proteins that were only detectable in our ultra-deep analysis. Further integration of 4 cortex and 4 CSF cohort proteomes highlighted 6 CSF biomarkers (SMOC1, C1QTNF5, OLFML3, SLIT2, SPON1, and GPNMB) that were consistently identified in at least 2 independent datasets. We also profiled CSF in the 5xFAD mouse model to validate amyloidosis-induced changes, and found consistent mitochondrial decreases (SOD2, PRDX3, ALDH6A1, ETFB, HADHA, and CYB5R3) in both human and mouse samples. In addition, comparison of cortex and serum led to an AD-correlated protein panel of CTHRC1, GFAP and OLFM3. In summary, 37 proteins emerged as potential AD signatures across cortex, CSF and serum, and strikingly, 59% of these were mitochondria proteins, emphasizing mitochondrial dysfunction in AD. Selected biomarker candidates were further validated by ELISA and TOMAHAQ assays. Finally, we prioritized the most promising AD signature proteins including SMOC1, TAU, GFAP, SUCLG2, PRDX3, and NTN1 by integrating all proteomic datasets.

Conclusions: Our results demonstrate that novel AD biomarker candidates are identified and confirmed by proteomic studies of brain tissue and biofluids, providing a rich resource for large-scale biomarker validation for the AD community.
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http://dx.doi.org/10.1186/s13024-020-00384-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382148PMC
July 2020

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

Mol Psychiatry 2020 Jul 6. Epub 2020 Jul 6.

James J Peters VA Medical Center, Research & Development, Bronx, NY, 10468, USA.

Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP) 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/PIP 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 PIP-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 PIP dyshomeostasis, cognitive deficits, and AD pathology.
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http://dx.doi.org/10.1038/s41380-020-0824-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785685PMC
July 2020

Gene expression meta-analysis reveals the down-regulation of three GABA receptor subunits in the superior temporal gyrus of patients with schizophrenia.

Schizophr Res 2020 06 4;220:29-37. Epub 2020 May 4.

Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel; Shalvata Mental Health Center, Affiliated with the Sackler School of Medicine, Tel-Aviv University, Israel. Electronic address:

One of the main theories accounting for the underlying pathophysiology of schizophrenia posits alterations in GABAergic neurotransmission. While previous gene expression studies of postmortem brain samples typically report the down-regulation of GABA related genes in schizophrenia, the results are often inconsistent and not uniform across studies. We performed a systematic gene expression analysis of 22 GABA related genes in postmortem superior temporal gyrus (STG) samples of 19 elderly subjects with schizophrenia (mean age: 77) and 14 matched controls from the Icahn school of Medicine at Mount Sinai (MSSM) cohort. To test the validity and robustness of the resulting differentially expressed genes, we then conducted a meta-analysis of the MSSM and an independent dataset from the Stanley Consortium of 14 STG samples of relatively young subjects with schizophrenia (mean age: 44) and 15 matched controls. For the first time, the findings showed the down-regulation of three GABA-receptor subunits of type A, GABRA1, GABRA2 and GABRB3, in the STG samples of subjects with schizophrenia, in both the elderly and the relatively young patients. These findings, as well as previous results, lend weight to the notion of a common upstream pathology that alters GABAergic neurotransmission in schizophrenia. GABRA1, GABRA2 and GABRB3 down-regulation may contribute to the pathophysiology and clinical manifestations of schizophrenia through altered oscillation synchronization in the STG.
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http://dx.doi.org/10.1016/j.schres.2020.04.027DOI Listing
June 2020

Large-scale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation.

Nat Med 2020 05 13;26(5):769-780. Epub 2020 Apr 13.

Departments of Neurology, Neuroscience and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Our understanding of Alzheimer's disease (AD) pathophysiology remains incomplete. Here we used quantitative mass spectrometry and coexpression network analysis to conduct the largest proteomic study thus far on AD. A protein network module linked to sugar metabolism emerged as one of the modules most significantly associated with AD pathology and cognitive impairment. This module was enriched in AD genetic risk factors and in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were elevated in cerebrospinal fluid in early stages of the disease. In this study of >2,000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brains that may serve as therapeutic targets and fluid biomarkers for the disease.
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http://dx.doi.org/10.1038/s41591-020-0815-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405761PMC
May 2020

Comparison of brain connectomes by MRI and genomics and its implication in Alzheimer's disease.

BMC Med 2020 02 6;18(1):23. Epub 2020 Feb 6.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Background: The human brain is complex and interconnected structurally. Brain connectome change is associated with Alzheimer's disease (AD) and other neurodegenerative diseases. Genetics and genomics studies have identified molecular changes in AD; however, the results are often limited to isolated brain regions and are difficult to interpret its findings in respect to brain connectome. The mechanisms of how one brain region impacts the molecular pathways in other regions have not been systematically studied. And how the brain regions susceptible to AD pathology interact with each other at the transcriptome level and how these interactions relate to brain connectome change are unclear.

Methods: Here, we compared structural brain connectomes defined by probabilistic tracts using diffusion magnetic resonance imaging data in Alzheimer's Disease Neuroimaging Initiative database and a brain transcriptome dataset covering 17 brain regions.

Results: We observed that the changes in diffusion measures associated with AD diagnosis status and the associations were replicated in an independent cohort. The result suggests that disease associated white matter changes are focal. Analysis of the brain connectome by genomic data, tissue-tissue transcriptional synchronization between 17 brain regions, indicates that the regions connected by AD-associated tracts were likely connected at the transcriptome level with high number of tissue-to-tissue correlated (TTC) gene pairs (P = 0.03). And genes involved in TTC gene pairs between white matter tract connected brain regions were enriched in signaling pathways (P = 6.08 × 10). Further pathway interaction analysis identified ionotropic glutamate receptor pathway and Toll receptor signaling pathways to be important for tissue-tissue synchronization at the transcriptome level. Transcript profile entailing Toll receptor signaling in the blood was significantly associated with diffusion properties of white matter tracts, notable association between fractional anisotropy and bilateral cingulum angular bundles (P = 1.0 × 10 and 4.9 × 10 for left and right respectively).

Conclusions: In summary, our study suggests that brain connectomes defined by MRI and transcriptome data overlap with each other.
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http://dx.doi.org/10.1186/s12916-019-1488-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003435PMC
February 2020

Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer's Disease Progression.

Neuron 2020 03 8;105(6):975-991.e7. Epub 2020 Jan 8.

Departments of Psychiatry and Neuroscience, The Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Mental Illness Research, Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY 10468, USA.

Alzheimer's disease (AD) displays a long asymptomatic stage before dementia. We characterize AD stage-associated molecular networks by profiling 14,513 proteins and 34,173 phosphosites in the human brain with mass spectrometry, highlighting 173 protein changes in 17 pathways. The altered proteins are validated in two independent cohorts, showing partial RNA dependency. Comparisons of brain tissue and cerebrospinal fluid proteomes reveal biomarker candidates. Combining with 5xFAD mouse analysis, we determine 15 Aβ-correlated proteins (e.g., MDK, NTN1, SMOC1, SLIT2, and HTRA1). 5xFAD shows a proteomic signature similar to symptomatic AD but exhibits activation of autophagy and interferon response and lacks human-specific deleterious events, such as downregulation of neurotrophic factors and synaptic proteins. Multi-omics integration prioritizes AD-related molecules and pathways, including amyloid cascade, inflammation, complement, WNT signaling, TGF-β and BMP signaling, lipid metabolism, iron homeostasis, and membrane transport. Some Aβ-correlated proteins are colocalized with amyloid plaques. Thus, the multilayer omics approach identifies protein networks during AD progression.
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http://dx.doi.org/10.1016/j.neuron.2019.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318843PMC
March 2020

C99 selectively accumulates in vulnerable neurons in Alzheimer's disease.

Alzheimers Dement 2020 02 6;16(2):273-282. Epub 2020 Jan 6.

Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.

Introduction: The levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer's disease (AD) progression. Therefore, it is likely that amyloid precursor protein and its proteolytic fragments other than amyloid b (Ab) contribute to the onset of AD.

Methods: We developed a sensitive assay adapted to the detection of C99, the direct precursor of b-amyloid. Three postmortem groups were studied: control with normal and stable cognition; patients with moderate AD, and individuals with severe AD. The amount of C99 and Aβ was quantified and correlated with the severity of AD.

Results: C99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, Aβ levels are increased in both vulnerable and resistant brain areas.

Discussion: These results raise the possibility that C99, rather than Aβ plaques, is responsible for the death of nerve cells in AD.
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http://dx.doi.org/10.1016/j.jalz.2019.09.002DOI Listing
February 2020

Is Alzheimer disease a failure of mobilizing immune defense? Lessons from cognitively fit oldest-old.

Dialogues Clin Neurosci 2019 03;21(1):7-19

Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mental Illness Research, Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, NY, USA.

Multifaceted evidence supports the hypothesis that inflammatory-immune mechanisms contribute to Alzheimer disease (AD) neuropathology and genetic association of several immune specific genes (TREM2, CR1, and CD33) suggests that maladaptive immune responses may be pivotal drivers of AD pathogenesis. We reviewed microglia-related data from postmortem AD studies and examined supporting evidence from AD animal models to answer the following questions: i) What is the temporal sequence of immune activation in AD progression and what is its impact on cognition? ii) Are there discordant, "primed", microglia responses in AD vs successful cognitive aging? iii) Does central nervous system (CNS) repair in aging depend on recruitment of the elements of cellular adaptive immune response such as effector T cells, and can the recruitment of systemic immune cells ameliorate AD neuropathology? iv) How effective are the immune-system-based therapeutic approaches currently employed for the treatment of AD?
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780355PMC
March 2019

CommonMind Consortium provides transcriptomic and epigenomic data for Schizophrenia and Bipolar Disorder.

Sci Data 2019 09 24;6(1):180. Epub 2019 Sep 24.

Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Schizophrenia and bipolar disorder are serious mental illnesses that affect more than 2% of adults. While large-scale genetics studies have identified genomic regions associated with disease risk, less is known about the molecular mechanisms by which risk alleles with small effects lead to schizophrenia and bipolar disorder. In order to fill this gap between genetics and disease phenotype, we have undertaken a multi-cohort genomics study of postmortem brains from controls, individuals with schizophrenia and bipolar disorder. Here we present a public resource of functional genomic data from the dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) of 986 individuals from 4 separate brain banks, including 353 diagnosed with schizophrenia and 120 with bipolar disorder. The genomic data include RNA-seq and SNP genotypes on 980 individuals, and ATAC-seq on 269 individuals, of which 264 are a subset of individuals with RNA-seq. We have performed extensive preprocessing and quality control on these data so that the research community can take advantage of this public resource available on the Synapse platform at http://CommonMind.org .
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http://dx.doi.org/10.1038/s41597-019-0183-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760149PMC
September 2019

Artificial intelligence in neuropathology: deep learning-based assessment of tauopathy.

Lab Invest 2019 07 15;99(7):1019-1029. Epub 2019 Feb 15.

Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Accumulation of abnormal tau in neurofibrillary tangles (NFT) occurs in Alzheimer disease (AD) and a spectrum of tauopathies. These tauopathies have diverse and overlapping morphological phenotypes that obscure classification and quantitative assessments. Recently, powerful machine learning-based approaches have emerged, allowing the recognition and quantification of pathological changes from digital images. Here, we applied deep learning to the neuropathological assessment of NFT in postmortem human brain tissue to develop a classifier capable of recognizing and quantifying tau burden. The histopathological material was derived from 22 autopsy brains from patients with tauopathies. We used a custom web-based informatics platform integrated with an in-house information management system to manage whole slide images (WSI) and human expert annotations as ground truth. We utilized fully annotated regions to train a deep learning fully convolutional neural network (FCN) implemented in PyTorch against the human expert annotations. We found that the deep learning framework is capable of identifying and quantifying NFT with a range of staining intensities and diverse morphologies. With our FCN model, we achieved high precision and recall in naive WSI semantic segmentation, correctly identifying tangle objects using a SegNet model trained for 200 epochs. Our FCN is efficient and well suited for the practical application of WSIs with average processing times of 45 min per WSI per GPU, enabling reliable and reproducible large-scale detection of tangles. We measured performance on test data of 50 pre-annotated regions on eight naive WSI across various tauopathies, resulting in the recall, precision, and an F1 score of 0.92, 0.72, and 0.81, respectively. Machine learning is a useful tool for complex pathological assessment of AD and other tauopathies. Using deep learning classifiers, we have the potential to integrate cell- and region-specific annotations with clinical, genetic, and molecular data, providing unbiased data for clinicopathological correlations that will enhance our knowledge of the neurodegeneration.
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http://dx.doi.org/10.1038/s41374-019-0202-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684013PMC
July 2019

The expression of long noncoding RNA NEAT1 is reduced in schizophrenia and modulates oligodendrocytes transcription.

NPJ Schizophr 2019 Jan 29;5(1). Epub 2019 Jan 29.

Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Oligodendrocyte (OLG)-related abnormalities have been broadly observed in schizophrenia (SZ); however, the etiology of these abnormalities remains unknown. As SZ is broadly believed to be a developmental disorder, the etiology of the myelin abnormalities in SZ may be related to OLG fate specification during development. Noncoding RNAs (ncRNAs) are an important part of multifaceted transcriptional complexes participating in neurogenic commitment and regulation of postmitotic cell function. The long ncRNA, NEAT1, is a structural component of paraspeckles (subnuclear bodies in interchromatin regions) that may control activity of developmental enhancers of OLG fate specification. Gene expression studies of multiple cortical regions from individuals with SZ showed strong downregulation of NEAT1 levels relative to controls. NEAT1-deficient mice show significant decreases in the numbers of OLG-lineage cells in the frontal cortex. To gain further insight into biological processes affected by NEAT1 deficiency, we analyzed RNA-seq data from frontal cortex of NEAT1 mice. Analyses of differentially expressed gene signature from NEAT1 mice revealed a significant impact on processes related to OLG differentiation and RNA posttranscriptional modification with the underlying mechanisms involving Wnt signaling, cell contact interactions, and regulation of cholesterol/lipid metabolism. Additional studies revealed evidence of co-expression of SOX10, an OLG transcription factor, and NEAT1, and showed enrichment of OLG-specific transcripts in NEAT1 purified chromatin isolates from human frontal cortex. Reduced nuclear retention of quaking isoform 5 in NEAT1 mice shed light on possible mechanism(s) responsible for reduced expression of OLG/myelin proteins and supported the involvement of NEAT1 in oligodendrocyte function.
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http://dx.doi.org/10.1038/s41537-019-0071-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386752PMC
January 2019

Assessment of somatic single-nucleotide variation in brain tissue of cases with schizophrenia.

Transl Psychiatry 2019 01 17;9(1):21. Epub 2019 Jan 17.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.

The genetic architecture of schizophrenia (SCZ) includes numerous risk loci across a range of frequencies and sizes, including common and rare single-nucleotide variants and insertions/deletions (indels), as well as rare copy number variants (CNVs). Despite the clear heritability of the disease, monozygotic twins are discordant for SCZ at a significant rate. Somatic variants-genetic changes that arise after fertilization rather than through germline inheritance-are widespread in the human brain and known to contribute to risk for both rare and common neuropsychiatric conditions. The contribution of somatic variants in the brain to risk of SCZ remains to be determined. In this study, we surveyed somatic single-nucleotide variants (sSNVs) in the brains of controls and individuals with SCZ (n = 10 and n = 9, respectively). From each individual, whole-exome sequencing (WES) was performed on DNA from neuronal and non-neuronal nuclei isolated by fluorescence activated nuclear sorting (FANS) from frozen postmortem prefrontal cortex (PFC) samples, as well as DNA extracted from temporal muscle as a reference. We identified an increased burden of sSNVs in cases compared to controls (SCZ rate = 2.78, control rate = 0.70; P = 0.0092, linear mixed effects model), that included a higher rate of non-synonymous and loss-of-function variants (SCZ rate = 1.33, control rate = 0.50; P = 0.047, linear mixed effects model). Our findings suggest sSNVs in the brain may constitute an additional component of the complex genetic architecture of SCZ. This perspective argues for the need to further investigate somatic variation in the brain as an explanation of the discordance in monozygotic twins and a potential guide to the identification of novel therapeutic targets.
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http://dx.doi.org/10.1038/s41398-018-0342-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336839PMC
January 2019

Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer's Disease.

J Mol Neurosci 2019 Apr 11;67(4):504-510. Epub 2019 Jan 11.

The Joseph Sagol Neuroscience Center Tel-hashomer, 52621, Ramat-Gan, Israel.

Disruption of brain insulin signaling may explain the higher Alzheimer's disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15-30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.
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http://dx.doi.org/10.1007/s12031-019-1257-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549496PMC
April 2019

Connectivity Analyses of Bioenergetic Changes in Schizophrenia: Identification of Novel Treatments.

Mol Neurobiol 2019 Jun 18;56(6):4492-4517. Epub 2018 Oct 18.

Department of Neuroscience, University of Toledo, Toledo, OH, USA.

We utilized a cell-level approach to examine glycolytic pathways in the DLPFC of subjects with schizophrenia (n = 16) and control (n = 16) and found decreased mRNA expression of glycolytic enzymes in pyramidal neurons, but not astrocytes. To replicate these novel bioenergetic findings, we probed independent datasets for bioenergetic targets and found similar abnormalities. Next, we used a novel strategy to build a schizophrenia bioenergetic profile by a tailored application of the Library of Integrated Network-Based Cellular Signatures data portal (iLINCS) and investigated connected cellular pathways, kinases, and transcription factors using Enrichr. Finally, with the goal of identifying drugs capable of "reversing" the bioenergetic schizophrenia signature, we performed a connectivity analysis with iLINCS and identified peroxisome proliferator-activated receptor (PPAR) agonists as promising therapeutic targets. We administered a PPAR agonist to the GluN1 knockdown model of schizophrenia and found it improved long-term memory. Taken together, our findings suggest that tailored bioinformatics approaches, coupled with the LINCS library of transcriptional signatures of chemical and genetic perturbagens, may be employed to identify novel treatment strategies for schizophrenia and related diseases.
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http://dx.doi.org/10.1007/s12035-018-1390-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584383PMC
June 2019

CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease.

Alzheimers Dement 2019 02 12;15(2):217-231. Epub 2018 Oct 12.

Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China. Electronic address:

Introduction: Altered cell cycle reentry has been observed in Alzheimer's disease (AD). Denticleless (DTL) was predicted as the top driver of a cell cycle subnetwork associated with AD.

Methods: We systematically investigated DTL expression in AD and studied the molecular, cellular, and behavioral endophenotypes triggered by DTL overexpression.

Results: We experimentally validated that CDT2, the protein encoded by DTL, activated cyclin-dependent kinases through downregulating P21, which induced tau hyperphosphorylation and Aβ toxicity, two hallmarks of AD. We demonstrated that cyclin-dependent kinases inhibition by roscovitine not only rescued CDT2-induced cognitive defects but also reversed expression changes induced by DTL overexpression. RNA-seq data from the DTL overexpression experiments revealed the molecular mechanisms underlying CDT2 controlled cell cycle reentry in AD.

Discussion: These findings provide new insights into the molecular mechanisms of AD pathogenesis and thus pave a way for developing novel therapeutics for AD by targeting AD specific cell cycle networks and drivers.
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http://dx.doi.org/10.1016/j.jalz.2018.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758558PMC
February 2019