Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
June 2020

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May 2020:

"Everything Hurts!" Distress in Semantic Variant Primary Progressive Aphasia

Metabolic Correlates of Prevalent Mild Cognitive Impairment and Alzheimer's Disease in Adults with Down Syndrome

Down Syndrome: Distribution of Brain Amyloid in Mild Cognitive Impairment

April 2020:

Cortical Thickness and its Associations with Age, Total Cognition and Education Across the Adult Lifespan

Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers

Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning

March 2020:

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Profilin 1 Delivery Tunes Cytoskeletal Dynamics Toward CNS Axon Regeneration

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

February 2020:

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

Exceptionally Low Likelihood of Alzheimer’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 Alzheimer’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 11C‐PBR28 PET

» Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons

July 2019:

» Alzheimer's Association International Conference (AAIC 2019)

June 2019:

» #1 CpG‐Related SNPs in the MS4A Region Have a Dose‐Dependent Effect on Risk of Late–Onset Alzheimer Disease

» #2 MFN2 Mutations in Charcot–Marie–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 β-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 Alzheimer’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 Alzheimer’s Human Brains

» #2 Semantic Network Function Captured by Word Frequency in Nondemented APOE ε4 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 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

Tau is not Necessary for Amyloid-Beta-Induced Synaptic and Memory Impairments

Ottavio Arancio, MD, PhD

The prevailing “amyloid cascade” hypothesis in Alzheimer’s disease (AD) research posits that amyloid-ß (Aß) and tau proteins are placed in series with Aβ upstream of tau, in a sort of trigger-bullet mechanism. This hierarchical profile in the chain of events leading to memory loss in AD is used as an explanation for the failures of many clinical trials, mostly targeting Aß. Two types of strategies are currently being implemented to overcome this obstacle. In one line of research, anti-Aß therapies are being administered prior to the overt disease manifestation. In the other, various aspects of tau pathology, including tau post-translational modifications, or tau levels, or tau aggregation status are being targeted. This hypothesis has more recently been challenged, however, by studies suggesting that Aß and tau act in parallel instead of being in series. If, in fact, the two proteins act in parallel, both anti-Aß and anti-tau therapies alone are doomed to fail. Solving this conundrum has been a central focus of research in the laboratory of Dr. Ottavio Arancio.

Aß and tau interaction in AD pathogenesis Figure: According to Dr. Arancio’s novel vision, both oligomers of Aß and tau exert a neurotoxic effect mediated by AßPP leading to synaptic and memory dysfunction. AßPP also mediates oligomers entrance into neurons and glial cells, a mechanism probably contributing to the spreading of the disease throughout the brain.

In the current manuscript, Dr. Arancio and colleagues, including former postdoc and first author Daniela Puzzo (University of Catania) report breakthrough findings to further inform this debate. Now published online in The Journal of Clinical Investigation, they demonstrate that neither exogenous oAß nor oTau need endogenous mouse tau to negatively impact the late phase of CA3-CA1 LTP and long-term hippocampal memory. Moreover, they find that tau suppression not only fails to reduce amyloid load in a mouse model of Aß deposition, but prompts the unraveling of a defect in basal neurotransmission in the model. These findings suggest that, at least for certain electrophysiological, behavioral, and histopathological aspects, Aß and tau act in parallel, and not in series as the amyloid cascade hypothesis predicts. Most importantly, Dr. Arancio and colleagues note, “our findings suggest that therapies targeting simultaneously Aß and tau might effectively improve LTP and memory. This might be achieved by combining anti-Aß and anti-tau therapeutics, or more likely, given that the physiological functions of these proteins might render these therapeutics not clinically viable, targeting substrates downstream of both peptides through either personalized medicine approaches or drugs acting on second messenger systems shared by the two proteins and relevant to synaptic plasticity and memory.”

Ottavio Arancio, MD, PhD
Professor of Pathology and Cell Biology (in the Taub Institute)

IL-27: An Endogenous Constitutive Repressor of Human Monocytes

Elizabeth M. Bradshaw, PhD    Wassim Elyaman, PhD
Elizabeth M. Bradshaw, PhD    Wassim Elyaman, PhD

The pleiotropic cytokine, Interleukin (IL)-27, has long been studied for its abilities to modulate T cell phenotypes in health and disease. As monocytes are known to be a major producer of IL-27, a new study by Drs. Elizabeth Bradshaw, Wassim Elyaman, and colleagues, including first author Dr. Michael Frangieh (Brigham and Women’s Hospital/Harvard), sought to examine the effect of endogenously produced IL-27 on human monocytes. As recently reported in the journal Clinical Immunology, they found that the addition of an anti-IL-27 neutralizing antibody increased the production of pro-inflammatory cytokines ex vivo with no additional stimuli needed (Figure 1). Neutralizing monocyte-derived IL-27 leads to monocytes that more readily polarize T cells to the Th17 phenotype, but have no effect on Th1 polarization. These findings suggest that IL-27 functions as an endogenous constitutive repressor, limiting pro-inflammatory cytokine production by keeping monocytes in a steady state. It also modifies the ability of monocytes to induce differentiation of CD4+ T cells to the Th17 phenotype. The locus that contains the IL27 gene has been linked to susceptibility for type 1 diabetes (T1D). Interestingly, ex vivo monocytes from subjects with T1D produce more IL-27.

Neutralization of endogenous IL-27
Figure 1: Neutralization of endogenous IL-27 leads to increased cytokine production. Negatively isolated monocytes from healthy subjects were incubated with an IL-27 neutralizing antibody for 40 hours. Supernatants were collected and cytokine production was measured using the Luminex platform. Each individual is represented as a dot.

As it becomes clearer that the immune system, both innate and adaptive, plays an important role in neurodegenerative diseases, such as Alzheimer and Parkinson disease, understanding pleiotropic cytokines, such as IL-27, in health and disease becomes a priority for neurodegenerative disease research. Unlike autoimmune diseases, where it is known that the immune system is inappropriately activated, in neurodegenerative diseases it is less clear if the immune system needs to be dampened down to reduce inflammation or ramped up to overcome immunosenescence brought on with age and disease. The receptor for IL-27 is widely expressed on immune cells, but also on non-immune cells including endothelial cells and astrocytes. Therefore, it is likely to have far reaching influence beyond modulating infiltrating T cell phenotypes. IL-27 itself is produced in the CNS by microglia, in addition to its peripheral production by circulating monocytes. Serum levels of IL-27 were found to be reduced in patients with Parkinson disease compared to healthy age matched individuals. Yet, among patients, levels were highest in individuals with severe disease compared to those with mild or moderate symptoms, as recently reported by Kouchaki et al. Understanding this master regulator could open up new avenues to understanding the role of the immune system in neurodegeneration.

Elizabeth M. Bradshaw, PhD
Adler Assistant Professor of Neurology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Institute for Genomic Medicine)

Wassim Elyaman, PhD
Assistant Professor of Neurological Sciences (in Neurology, the Taub Institute and the Institute for Genomic Medicine)

Subgingival Microbiome and Clinical Periodontal Status in an Elderly Cohort: The WHICAP Ancillary Study of Oral Health

James M. Noble, MD, MS

Over the past 20 years, the Washington Height-Inwood Columbia Aging Project has serially assessed approximately 6,000 participants over the age of 65 years with respect to medical, social, and health behavior histories, general medical exams, and neuropsychological testing. The WHICAP Ancilliary Study of Oral Health, led by Dr. James Noble, is an NIH-funded cohort study involving a subset of 1,130 individuals from the WHICAP cohort, aimed at studying the relationship between periodontitis—a marker of systemic inflammation—and cognitive decline.

In the current study, now published online in the Journal of Periodontology, Dr. Noble and colleagues, including first author Dr. Panos Papapanou (Director of the Division of Periodontics, Columbia College of Dental Medicine) and Anne-Catrin Uhlemann (Director of the Columbia Microbiome Core Facility), present data on the subgingival microbiome of the dentate participants of the ancillary study, and of the association of metrics of bacterial relative abundance and diversity with clinical periodontal status. The investigators obtained and analyzed plaque samples by means of next generation sequencing to carry out a comprehensive identification of the prevalent bacterial taxa as well as to calculate relative abundance and diversity metrics in different states of periodontal health and disease. They classified the clinical periodontal status (see figure) using both a four-level ordinal scale that is widely used in epidemiological studies (the CDC/AAP classification) and a continuous measure of periodontitis extent and severity based on the percentage of teeth per participant with pockets ≥4 mm deep.

Figure 3A: Periodontal disease groups relative to indices of abundance and diversity of periodontal microbes.

Findings from Papapanou et al. indicate that 1) the most abundant and/or differentially enriched taxa that emerged among the distinct periodontal phenotypes in this cohort of elderly individuals were generally similar to those described in the literature for younger age groups; and 2) subgingival microbial diversity increased in parallel with the severity and extent of periodontitis.

This research is part of a broader, ongoing study exploring cross-sectional and longitudinal indicators of cognitive change relative to these periodontal markers of disease. Preliminary studies leading to this current project were supported by the Department’s T32 neuroepidemiology fellowship training grant and Taub pilot research support.

James M. Noble, MD, MS
Associate Professor of Neurology (in the Taub Institute and the Sergievsky Center) at the Columbia University Medical Center

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