Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
March 2020

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February 2020:

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Exceptionally Low Likelihood of Alzheimerā€™s Dementia in APOE2 Homozygotes from a 5,000-Person Neuropathological Study

January 2020:

Microglial Activation, but not Tau Pathology, is Independently Associated with Amyloid Positivity and Memory Impairment

CRISPR/Cas9 Editing of APP C-Terminus Attenuates β-Cleavage and Promotes α-Cleavage

December 2019:

Activity-Dependent Nucleation of Dynamic Microtubules at Presynaptic Boutons Controls Neurotransmission

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

Sleep Fragmentation, Microglial Aging, and Cognitive Impairment in Adults with and Without Alzheimer's Dementia

November 2019:

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

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

October 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

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Estela Area Gomez, PhD    Karen Duff, PhD    Tal Nuriel, PhD

While much of the research on the association of the apolipoprotein E4 (APOE4) allele and Alzheimerā€™s disease (AD) risk has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of AĪ², there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of the diverse effects that APOE4 expression has on the brain, the laboratories of Dr. Tal Nuriel, Dr. Estela Area Gomez, and Dr. Karen Duff teamed up to perform a series of investigations in aged APOE mice.

Figure 3: Seahorse analysis reveals decreased mitochondrial respiration in the cortex and hippocampus, but not in the EC, of aged male APOE4 mice. Seahorse analysis was performed in order to analyze the effects of differential APOE isoform expression on mitochondrial respiration in mitochondria that were isolated from the cortex (Ctx), hippocampus (Hip) and EC of 20-month-old APOE mice (2 APOE4/4 males, tissues pooled vs. 2 APOE3/3 males, tissues pooled). (A) The oxygen consumption rate (OCR) from each region shows decreased mitochondrial respiration in the Ctx and Hip, but not the EC of the aged APOE4/4 mice. (B,C) Bar graphs showing the average OCR from (B) State 3 and for (C) the Respiration Control Ratio (RCR; state 3 u/state 4o) in each region of the APOE4/4 mice, as a percentage of the APOE3/3 OCR from the equivalent tissues. The dotted blue line represents the normalized levels in the APOE3/3 tissues. (**denotes p < 0.01; ***denotes p < 0.001; ****denotes p < 0.0001).

As reported this month in Scientific Reports, they found that while aged APOE4 mice possess bioenergetic deficits in the hippocampus and cortex, the entorhinal cortex (EC) of these mice appears to possess unique counterbalancing mechanisms that allows it to resist these APOE4-associated decreases in mitochondrial respiration. Specifically, they observed increased coupling of oxygen consumption with ATP production in the EC of aged APOE4 mice, which appears to be modulated by an upregulation of multiple mitochondrial nutrient shuttling systems. Finally, the authors hypothesize that this increased coupling efficiency may give way to increased ROS production, which may in turn play a causative role in the early AD pathology observed in the EC during disease pathogenesis.

Estela Area Gomez, PhD
Assistant Professor in the Department of Neurology

Tal Nuriel, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute) at the CUMC

Profilin 1 Delivery Tunes Cytoskeletal Dynamics Toward CNS Axon Regeneration

Francesca Bartolini, PhD

Adult vertebrate central nervous system (CNS) axons are unable to regenerate. This failure results from the highly inhibitory extrinsic environment at the injury site, and the intrinsic inability of CNS axons to reactivate actin and microtubule remodeling to form a competent growth cone from a dystrophic growth-incompetent retraction bulb. In the present study, an international team of investigators, including Taub faculty member Dr. Francesca Bartolini, use in vivo models with high and low regenerative capacities, followed by gain- and loss-of-function analysis, to identify the actin-binding protein profilin 1 (Pfn1) as a critical regulator of actin and microtubule dynamics that supports axon regrowth and regeneration in mouse models of nerve injury. Peripheral nerve injury leads to increased Pfn1 activity in growth cones, where it promotes cytoskeletal dynamics that enhance axon regeneration. Loss of Pfn1, on the other hand, impairs axon growth in both peripheral and spinal cord injury as well as reduces axonal and dendritic growth in cultured hippocampal neurons. As published in The Journal of Clinical Investigation, the authors examine the mechanism of cytoskeletal regulation and demonstrate that in the growth cone, Pfn1 interferes both with microtubule growth and invasion into filopodia through cooperation with formins, a family of actin nucleators and modulators of microtubule stability. Importantly, systemic delivery of Pfn1 in mice promotes axon regeneration of injured sciatic nerves, and of transected ascending spinal cord tracts (see the accompanying Figure), demonstrating the potential of Pfn1-targeting therapies to enhance nerve regrowth and functional recovery after injury.


Mutations in Pfn1 have been associated with neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), further underscoring the role of Pfn1 in maintaining a healthy neuronal architecture. The findings in this paper demonstrate that modulation of Pfn1 levels and activity is instrumental to achieve a regenerative phenotype and suggest that AAV-mediated delivery of active Pfn1 and/or identification of in vivo modulators of Pfn1 activity, should be considered for the treatment of the injured nervous system as well as neurodegenerative disease.

Francesca Bartolini, PhD
Assistant Professor of Pathology and Cell Biology at the CUMC

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls Across Multiple Cohorts

Philip L. De Jager, MD, PhD
Philip L. De Jager, MD, PhD

Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus 6 (HHV-6) in particular, in Alzheimerā€™s disease (AD). Thus, Dr. Philip L. De Jager and members of his lab collaborated with colleagues from the National Institute of Neurological Disorders and Stroke (NINDS) to screen for HHV-6 detection across three independent AD brain repositories.

First, using the Broad Institute PathSeq tool, RNA sequencing datasets from the Mount Sinai Brain Bank and the Religious Orders Study/Memory and Aging Project (ROSMAP) were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses. Next, using a highly sensitive and precise digital droplet polymerase chain reaction (ddPCR) platform, DNA samples from 711 AD and control brains obtained from ROSMAP and the Johns Hopkins Brain Resource Center were probed for PCR reactivity to HHV-6A and/or HHV-6B.

Kaplanā€“Meier curves Figure 3: HHV-6 Detection via ddPCR across Disease Statuses. The HHV-6B viral load, in copies per 106 cells, is compared between AD and non-AD samples in both the ROSMAP and JHBRC cohorts. Viral load did not differ significantly across groups (one-way ANOVA p = 0.41). The frequency of detection of HHV-6A and HHV-6B did not differ between AD and non-AD samples (Ļ‡2 p = 0.81), with frequencies all remaining well below 10% in each disease cohort. Data are represented as mean Ā± SD.

As published in Neuron, these direct methods of viral detection did not support an association between HHV-6 and AD but also did not rule it out. According to the authors, ā€œif viruses (and HHV-6 in particular) do play a role in AD pathogenesis, then the agents may no longer be present in a form that can be PCR amplified or sufficiently expressed. Rather, these virus(es) may be associated with an earlier ā€œtriggeringā€ event or be present at copy numbers below the limit of laboratory detection.ā€

Philip L. De Jager, MD, PhD
Weil-Granat Professor of Neurology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Precision Medicine Initiative)

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