Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
July 2020





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June 2020:

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

IL-27: An Endogenous Constitutive Repressor of Human Monocytes

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


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




Endothelial Activation of Caspase-9 Promotes Neurovascular Injury in Retinal Vein Occlusion

Members of the Troy Laboratory
Members of the Troy Laboratory (from left to right), 1st row: Maria Avrutsky, Carol Troy (PI), Crystal Colon Ortiz; 2nd row: Kendra Johnson, Anna Potenski, Jackie Lawson; 3rd row: Monica Choi, Crystal Collier, James Belarde; 4th row: Jade Smart, Claire Chen

Regulation of the neurovascular unit is an active area of research interest in multiple disciplines because many neurologic disorders exhibit both neuronal dysfunction and loss of vascular integrity. However, the mechanistic relation of these phenomena has not been explicated. Studies have been hampered by the lack of available animal models that enable real-time live imaging of the neurovascular unit. Utilizing in vivo imaging of the mouse retina, Dr. Carol Troy and colleagues, including first author Dr. Maria Avrutsky, have investigated the mechanistic relation of vascular and neuronal injury, employing a mouse retinal vein occlusion (RVO) model of hypoxia-ischemia.

Dr. Troy has an enduring interest in understanding the role of the caspase family of proteases in the mature nervous system. Her group’s recent publication in Nature Communications establishes caspase-9 mediated endothelial cell signaling as the pivotal event in the subsequent loss of vascular integrity and neuronal dysfunction. Caspase-9 activity has been tightly associated with the initiation of the intrinsic apoptosis pathway, and far less is known about caspase biology in nonapoptotic processes. This work shows that endothelial cells play an active role in maintaining vascular and neuronal health, and that nonapoptotic activation of caspase-9 in endothelial cells promotes neurodegeneration.

Figure 7: Endothelial caspase-9 mediates neuronal injury following RVO
Figure 7: Endothelial caspase-9 mediates neuronal injury following RVO
A. Retinal cross-sections 24hr post-RVO from Casp9 WT and Casp9 iEC KO mice immunostained for cl-caspase-9 (blue), caspase-7 (green), isolectin (red) and DAPI (white). White arrows = vessels expressing cl-caspase-9 and caspase-7. Scale bar=25µm.
E. Retinal cross-sections of Casp9 WT (n=11) and Casp9 iEC KO (n=6) eyes 24hr post-RVO, stained for TUNEL (green), isolectin (red) and DAPI.
cl-casp9, cl-caspase-9; casp7, caspase-7. Source data are provided as a Source Data file.

As recently featured on the CUIMC Newsroom, this work also provides a translational approach to developing interventions for neurovascular dysfunction: the authors identify a tractable target for treatment of hypoxic and ischemic injury, use clinically relevant ophthalmic imaging to track changes in retinal pathology, and demonstrate topical drug delivery to the retina via eye drops. Topical drug delivery presents a potential paradigm shift for treatments of retinal disease, since current therapies require clinician-administered intravitreal injections.

By correlating clinically-relevant measures of retinal injury and immunohistochemical analysis, the authors demonstrate how the retina is a powerful in vivo model to study regulation of neuronal health and barrier integrity. This model allows examination of the neurovascular unit in a physiologic setting, providing ease of use and translational relevance. They also demonstrate a simple-to-use and noninvasive strategy to deliver pharmacologic interventions into retinal tissues. This approach can be applied to a wide variety of proteins and peptides, and may be of interest to basic scientists as a research tool to interrogate the neurovascular unit and to clinicians as a potential noninvasive therapeutic.

Carol M. Troy, MD, PhD
Professor of Pathology and Cell Biology and Neurology (in the Taub Institute) cmt2@cumc.columbia.edu



Proteomic Profiles for Alzheimer's Disease and Mild Cognitive Impairment Among Adults with Down Syndrome Spanning Serum and Plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) Study

Dr. Schupf    Joseph H. Lee, DrPH
Nicole Schupf, PhD    Joseph H. Lee, DrPH

The use of blood-based biomarkers as a screening tool for the presence of neurodegenerative disease have gained considerable support for application in adults with Down syndrome (DS) for being less invasive and burdensome in clinical practice and clinical trials. Unlike in the general AD population where a serum proteomic profile has been successfully validated, only one study has examined the utility of blood biomarkers in adults with DS.

A new study co-authored by Taub faculty members Drs. Nicole Schupf and Joseph Lee, led by Dr. Sid O’Bryant of the University of North Texas Health Sciences Center, is the first to apply a panel of inflammatory proteomic markers to adults with DS. As recently published by Petersen et al. in Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring, their results reveal that the proteomic profiles derived from both serum and plasma produced excellent detection accuracy to distinguish prevalent MCI and AD from those without any signs of dementia. Detection accuracy reached an area under the curve (AUC) ranging from 95% to 98% for serum and plasma proteomic profiles for distinguishing those with MCI and AD from those without. The rates of accuracy were comparable to those observed in the general population.

This study identified sets of inflammatory proteomic markers (e.g., B2M, TNF-𝛼, IL-5, IL-10, CRP, IL-18, and IL-6) from serum and plasma that distinguished those with MCI-DS and DS-AD from those who were cognitively stable. Current work is focused on developing preclinical proteomic profiles to predict incident MC-DS and DS-AD to allow for future therapeutic interventions before irreversible cognitive deterioration has occurred.

Nicole Schupf, PhD
Professor of Epidemiology (in Neurology, Psychiatry, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)
ns24@cumc.columbia.edu

Joseph H. Lee, DrPH
Professor of Epidemiology (in the Gerturde H. Sergievsky Center and Taub Institute)
jhl2@cumc.columbia.edu



Cognitive Tests aid in Clinical Differentiation of Alzheimer's Disease Versus Alzheimer's Disease with Lewy Body Disease: Evidence from a Pathological Study

Stephanie Cosentino, PhD    Yaakov Stern, PhD
Stephanie Cosentino, PhD    Yaakov Stern, PhD

Although Alzheimer’s disease (AD) and Lewy body disease (LBD) have unique pathological profiles, patients commonly present with pathologies characteristic of both diseases. Clinical differentiation between AD versus AD plus LBD remains relatively imprecise. Drs. Stephanie Cosentino, Yaakov Stern, Yian Gu, Sylvia Chapman, and colleagues sought to further the understanding of neuropsychological differences across AD versus AD plus LBD by examining group differences in performance across a range of neuropsychological tests. These included measures of visuoconstruction, processing speed, memory, language, attention, and executive functioning in 51 participants with postmortem diagnoses of AD (n=34) versus AD plus LBD (n=17). They further assessed the ability of tests that differed at the group level to classify individuals into pathologic group, while accounting for noncognitive symptoms (i.e., hallucinations and extrapyramidal signs) that are often present in individuals with AD who have comorbid LBD.


Figure 4: ROC curve of processing speed and visuoconstruction measures

As recently reported in Alzheimer’s & Dementia, they found that AD plus LBD was characterized by relatively greater impairments in executive functioning, processing speed, and visuoconstructional abilities. Groups did not differ in memory or semantic processing. Their results offer guidance in the selection and interpretation of neuropsychological tests to be used in the differential diagnosis of early dementia.

Stephanie Cosentino, PhD
Associate Professor of Neuropsychology (in Neurology, the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)
sc2460@cumc.columbia.edu

Yaakov Stern, PhD
Professor of Neuropsychology (in Neurology, in Psychiatry, in the Gertrude H. Sergievsky Center, and in the Taub Institute)
ys11@cumc.columbia.edu




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