Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
Best Poster Presentations
Taub Institute Retreat November 2018

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November 2018:

» #1 Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

» #2 An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

» #3 Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility

September 2018:

» #1 Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

» #2 Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE ε4 Haplotype Status: A Community-Based Cohort Study

August 2018:

» #1 A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research

» #2 An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

» #3 Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults

July 2018:

» #1 Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

» #2 Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease

June 2018:

» #1 Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

» #2 Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices

May 2018:

» #1 Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

» #2 Oligomeric Aβ1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons

April 2018:

» #1 Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

» #2 Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion

March 2018:

» #1 Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

» #2 White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes

February 2018:

» #1 ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

» #3 A Transcriptomic Atlas of Aged Human Microglia

January 2018:

» #1 Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

» #2 An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population

December 2017:

» #1 Neuronal Hyperactivity Due to Loss of Inhibitory Tone in APOE4 Mice Lacking Alzheimer's Disease-Like Pathology
» The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

» #2 The Historical Progression from ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia

November 2017:

» First Place: A CSF Proteomic Screen Links Retromer to Alzheimer's Pathogenic Pathways and Suggests Endosomal-Trafficking Biomarkers

» First Place: Microglia Identity in the Aged and AD Human Brain

October 2017:

» #1 Intra-Axonal Synthesis of SNAP25 is Required for the Formation of Presynaptic Terminals

» #2 Increased Localization of APP-C99 in Mitochondria-associated ER Membranes Causes Mitochondrial Dysfunction in Alzheimer Disease

September 2017:

» #1 Stabilization of Dynamic Microtubules by mDia1 Drives Tau-dependent Aβ1-42 Synaptotoxicity

» #2 An xQTL Map Integrates the Genetic Architecture of the Human Brain's Transcriptome and Epigenome

August 2017:

» #1 Abolishing Tau Cleavage by Caspases at Aspartate421 Causes Memory/Synaptic Plasticity Deficits and Pre-Pathological Tau Alterations

» #2 Mediterranean Diet and Cognitive Health: Initial Results from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD)

July 2017:

» #1 Abnormal Neurofilament Inclusions and Segregations in Dorsal Root Ganglia of A Charcot-Marie-Tooth Type 2E Mouse Model

» #2 LTP and Memory Impairment Caused by Extracellular Aβ and Tau Oligomers is APP-Dependent

June 2017:

» #1 Post translational Remodeling of Ryanodine Receptor Induces Calcium Leak Leading to Alzheimer's Disease like Pathologies and Cognitive Deficits

» #2 Neuropathologic Features of TOMM40 '523 Variant on Late-Life Cognitive Decline

May 2017:

» #1 Memory-Enhancing Effects of GEBR-32a, a New PDE4D Inhibitor Holding Promise for the Treatment of Alzheimer's Disease

» #2 An Approach to Studying the Neural Correlates of Reserve

April 2017:

» #1 Brain Atrophy Can Introduce Age-Related Differences in BOLD Response

» #2 Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities

March 2017:

» #1 Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes

» #2 Polygenic Risk Scores in Familial Alzheimer Diseases

February 2017:

» #1 Local Synthesis of Dynein Cofactors Matches Retrograde Transport to Acutely Changing Demands

» #2 Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study

January 2017:

» #1 Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease

» #2 Novel Genetic Loci Underlying Human Intracranial Volume Identified Through Genome-Wide Association

» #3 Relation of Dysglycemia to Structural Brain Changes in a Multiethnic Elderly Cohort

NSUN2 is Dysregulated in Alzheimer’s Disease

Pictured (from left to right): Dr. Jennifer J. Manly, Yoon A. Kim, and Dr. Inbal Israely

Figure: Investigating the role of NSUN2 in Alzheimer's disease.

Yoon A. Kim1,2 & Ismael Santa-Maria1,2
1Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY.
2Taub Institute for Research on Alzheimer's Disease and the Aging Brain.

Accumulation of extracellular amyloid beta (Aβ) deposits, intracellular neuronal tangles composed of hyperphosphorylated tau and synaptic loss are the main hallmarks of Alzheimer’s disease (AD), the most prevalent form of dementia. Currently, the molecular basis of AD is unclear. However, several studies support that altered microRNA (miRNA) expression and/or function plays an important role in AD pathogenesis. However, the mechanisms governing how miRNAs are regulated in the brain are poorly understood. RNA methylation is a prevalent posttranscriptional modification that regulates accuracy of translation initiation, RNA stability, biogenesis and processing of RNA. Historically, it has been shown that methylation occurs on transfer RNA, ribosomal RNA and messenger RNA. Recently, methylation of miRNAs has also been found. However, methyltransferases involved in this process are still under investigation. NSUN2 is one the few known brain-enriched methyltransferases in higher eukaryotes that is able to mediate methylation of miRNAs. Moreover, the loss of NSUN2 in Drosophila and mouse models causes memory and learning deficits, indicating a potential role of NSUN2 in cognitive function. Furthermore, in humans, mutations in the NSUN2 gene cause intellectual disability. Interestingly, the role of microRNA methylation in AD pathogenesis has not been reported. Here, our data supports dysregulation of NSUN2 in post-mortem brain tissue from AD patients when compared to healthy controls. In addition, we found that oligomeric Aβ induces both dysregulation of NSUN2 and changes in tau proteostasis in primary neuronal cultures. Furthermore, bioinformatic analysis shows predicted methylation sites in miRNAs that have been implicated in AD, supporting a possible link between NSUN2 dysfunction, microRNAs and AD pathogenesis.

Yoon A. Kim
Student, Graduate Program in Pathobiology and Molecular Medicine
Columbia University Irving Medical Center

High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases

Pictured (from left to right): Dr. Inbal Israely, Samuel Resnick, and Dr. Jennifer J. Manly

Figure: DNA-barcoded libraries allow us to multiplex high-throughput screening by studying multiple disease models in the same screen. This application towards neurodegenerative diseases gives us the ability to rapidly and efficiently identify novel phenotypic modifiers for a wide range of genes implicated in neurodegeneration.

Samuel Resnick 1,2,3 & Alejandro Chavez 1,2

1 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University
2 Department of Pathology and Cell Biology, Columbia University
3 Columbia University Vagelos College of Physicians and Surgeons

The ability to assay multiple cellular models of disease in parallel against a wide variety of experimental conditions in lieu of traditional one-at-a-time approaches would greatly increase the scope of known cellular responses in disease. Here, we develop a scalable, inexpensive, and multiplexed approach to identify genetic modifiers of aggregation-prone proteins implicated in a variety of neurodegenerative diseases during a single experiment. Using DNA-barcoded yeast, we screen upwards of 4000 potential interactions between aggregation-prone proteins and molecular chaperones and subsequently identify numerous interactions that rescue aggregation-prone protein mediated cellular toxicity. These hits are comprised of previously reported chaperone-aggregate interactions in addition to novel interactions that will be followed up in mammalian models of disease.

Samuel Resnick
Student, Graduate School of Arts and Sciences
Columbia University Irving Medical Center

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