Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
Best Poster Presentations
Taub Institute Retreat November 2019

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November 2019:

» Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

» Promotion of Axon Growth by the Secreted End of a Transcription Factor

September 2019:

» Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume

» Synaptic and Memory Dysfunction Induced by Tau Oligomers is Rescued by up-regulation of the Nitric Oxide Cascade

» Medicaid Contributes Substantial Costs to Dementia Care in an Ethnically Diverse Community Population

August 2019:

» Neuroinflammation in Frontotemporal Lobar Degeneration Revealed by 11Cā€PBR28 PET

» Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons

July 2019:

» Alzheimer's Association International Conference (AAIC 2019)

June 2019:

» #1 CpGā€Related SNPs in the MS4A Region Have a Doseā€Dependent Effect on Risk of Lateā€“Onset Alzheimer Disease

» #2 MFN2 Mutations in Charcotā€“Marieā€“Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics

May 2019:

» #1 Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease

» #2 Brain Biomarkers and Cognition Across Adulthood

April 2019:

» #1 Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers

» #2 Brain Arterial Dilatation and the Risk of Alzheimer's Disease

March 2019:

» #1 Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of Ī²-Amyloid Precursor Protein

» #2 FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome

February 2019:

» #1 Effect of Aerobic Exercise on Cognition in Younger Adults: A Randomized Clinical Trial

» #2 Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimerā€™s Models

January 2019:

» #1 A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

» #2 Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain

December 2018:

» #1 Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimerā€™s Human Brains

» #2 Semantic Network Function Captured by Word Frequency in Nondemented APOE Īµ4 Carriers

November 2018:

» First Place: NSUN2 is Dysregulated in Alzheimer's Disease

» First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases

October 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 AĪ²42, 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 Īµ4 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 AĪ²1-42 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

Studying Biochemical Mechanisms of Protective Gene Variants in Isogenic Stem Cell-derived Early Onset Alzheimerā€™s Disease Models

R. Patel, S. Miller, A. Ashok, J. Lee, A. Sproul

Dr. Ronak Patel
Ronak Patel, PhD

The prevailing theory to explain the etiology of Alzheimerā€™s disease (AD) is the amyloid cascade hypothesis, although attempts to derive disease-modifying therapies that target canonical Abeta production pathways or Abeta itself have failed thus far. The rise in the number of AD patients as people live longer warrants the need for alternative approaches to modify disease progression. Significant progress has been made to identify genes related to AD pathogenesis to understand the mechanism of degeneration. Identification of protective/risk variants and their underlying mechanism is equally important to elucidate novel therapeutic targets against AD. A previous study by Drs. Lee, Mayeux and other colleagues have identified protective variants from genetic screening of a cohort of Puerto Rican families carrying the PSEN1 G206A mutation that is sufficient to cause early onset AD. Single Nucleotide Polymorphisms (SNPs) in SNX25, PDLIM3, SORBS2, SH3RF3 and NPHP1 genes were significantly correlated to age at onset of AD (Lee et. al, JAMA Neurol., 2015). Our goal is to uncover biochemical mechanisms of protection by the aforementioned gene variants in a PSEN1 G206A background by using human neurons derived from isogenic PSEN1 mutant and control pluripotent stem cells (PSCs).


Approach: We have knocked in the PSEN1 G206A mutation into two control PSC lines (H9 and IMR90) using CRISPR-Cas9. Neurons differentiated from PSEN1 G206A and isogenic control PSCs are being used for gain-of-function (overexpression, CRISPRa) and loss-of-function (siRNA) experiments for protective gene variants in neurons derived by Ngn2-mediated transdifferentiation. Amyloid precursor protein (APP) processing and tau levels will be assessed and RNAseq and other ā€œOMICā€ assays will be performed to further understand the pathways involved in mechanism of protective gene variants.

Preliminary Results: Our initial efforts have focused on understanding the role of a protective SNP rs6542814 in SH3RF3/POSH2, which can delay AD onset by 9.3 years in PSEN1 G206A carriers. SH3RF3/POSH2ā€™s paralog POSH has been established as a pro-apoptotic JNK pathway scaffold that facilitates activation of AP-1 (Xu et. al, EMBO 2003). We predicted that a protective SNP in SH3RF3 would reduce its expression. In agreement with this hypothesis, in silico analysis showed that rs6542814 disrupts a binding site for the general transcription factor TFII-I. Although JNK signaling affects many AD-related cellular processes, we became particularly interested assessing effects on APP transcription in light of recent work demonstrating exogenous APOE4 drives APP transcription through AP-1 and non-canonical ERK signaling (Huang et al., Cell 2017). Overexpression of SH3RF3/POSH2 in HEK293T cells drives JNK activation and leads to increased APP transcription. Conversely, siRNA mediated knockdown of SH3RF3/POSH2 in stem cell derived neurons reduces APP transcription. The potential importance of regulation of APP transcription by genetic modifiers of AD is underscored by rare APP triplication that is sufficient to cause early onset AD as well as the high prevalence of dementia in individuals with Down syndrome.

Ronak Patel, PhD
Postdoctoral Research Scientist in the Taub Institute

Glial Heterogeneity in Normal Human Cortex and Huntington Disease Interrogated Through Single Cell Nuclear RNA Sequencing

Dr. Osama Al Dalahmah
Osama Al Dalahmah, MD, DPhil


O. Al Dalahmah, A. Sosunov, I. Adorjan, J. E. Goldman

The heterogeneity of CNS glia in the human CNS in normal and pathological conditions requires much further study. To address human glial heterogeneity, we examined transcriptional profiles of control (patients without neurological disease or neuropathology) and advanced Huntington Disease (HD) cingulate cortices using single cell nuclear RNAseq (scnRNAseq) with nuclei isolated from frozen control and HD autopsy tissues. Unsupervised and supervised cluster analysis and classification showed a number of discrete cell clusters corresponding to astrocytes, neurons, oligodendrocytes (OL), OPCs, microglia and endothelial cells. For all cell types, control and HD populations were heterogeneous, and also segregated preferentially between HD and controls. We found a novel signature for reactive HD astrocytes, including a downregulation of NOTCH signaling and fatty acid synthesis genes, and an upregulation of MHC class I and metallothionein (MT) genes. We found 3 different reactive astrocyte ā€œstatesā€, defined by differences in expression of SLC1A2, MTs and GFAP. Astrocytes did not show up-regulation of C3 transcript or C3 protein assessed by immunostaining, but in contrast, astrocytes of the neostriatum of the same brains did upregulate C3 protein, suggesting that different reactions occur in different stages of degenerative pathology in HD. Among OLs we found a large population of OLs in HD that showed marked down-regulation of myelin genes. The HD microglia up-regulated SPP1 (Osteopontin, matrix formation and promotion of inflammation) and HAMP (Hepcidin, iron accumulation), among other genes. All cells upregulated a variety of heat shock protein genes. scnRNAseq provides a technology for interrogating cell-type specific gene expression in the control and pathological CNS from banked brain samples, and the results may identify subset-specific therapeutic targets.

Osama Al Dalahmah, MD, DPhil
Postdoctoral Neuropathology Fellow in the Department of Pathology and Cell Biology

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