Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
Best Poster Presentations
Taub Institute Retreat November 2022

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October 2022:

Clearance of an Amyloid-Like Translational Repressor is Governed by 14-3-3 Proteins

Diet Moderates the Effect of Resting State Functional Connectivity on Cognitive Function

Longitudinal Patterns of Cortical Atrophy on MRI in Patients With Alzheimer Disease With and Without Lewy Body Pathology

September 2022:

Crosstalk Between Acetylation and the Tyrosination/Detyrosination Cycle of α-Tubulin in Alzheimer's Disease

Deep Learning of MRI Contrast Enhancement for Mapping Cerebral Blood Volume from Single-Modal Non-Contrast Scans of Aging and Alzheimer's Disease Brains

Socioeconomic Status, Biological Aging, and Memory in a Diverse National Sample of Older US Men and Women

August 2022:

Retromer Deficiency in Tauopathy Models Enhances the Truncation and Toxicity of Tau

Aβ42 Oligomers Trigger Synaptic Loss Through CAMKK2-AMPK-Dependent Effectors Coordinating Mitochondrial Fission and Mitophagy

July 2022:

GW5074 Increases Microglial Phagocytic Activities: Potential Therapeutic Direction for Alzheimer's Disease

Cerebral Amyloid Angiopathy Interacts with Neuritic Amyloid Plaques to Promote Tau and Cognitive Decline

Amyloid, Cerebrovascular Disease, and Neurodegeneration Biomarkers Are Associated with Cognitive Trajectories in a Racially and Ethnically Diverse, Community-Based Sample

June 2022:

Genotype-Phenotype Correlation of T Cell Subtypes Reveals Senescent and Cytotoxic Genes in Alzheimer's Disease

Single Cell/Nucleus Transcriptomics Comparison in Zebrafish and Humans Reveals Common and Distinct Molecular Responses to Alzheimer's Disease

May 2022:

FMNL2 Regulates Gliovascular Interactions and Is Associated with Vascular Risk Factors and Cerebrovascular Pathology in Alzheimer’s Disease

Molecular Insights into Cell Type-Specific Roles in Alzheimer's Disease: Human Induced Pluripotent Stem Cell-Based Disease Modeling

Effects of Eph/Ephrin Signalling and Human Alzheimer's Disease-Associated EphA1 on Drosophila Behaviour and Neurophysiology

April 2022:

Progranulin Mutations in Clinical and Neuropathological Alzheimer's Disease

Wolframin is a Novel Regulator of Tau Pathology and Neurodegeneration

Clinical Trajectories at the End of Life in Dementia Patients With Alzheimer Disease and Lewy Body Neuropathologic Changes

March 2022:

Homotypic Fibrillization of TMEM106B Across Diverse Neurodegenerative Diseases

Correlation of Plasma and Neuroimaging Biomarkers in Alzheimer's Disease

Probing the Proteome to Explore Potential Correlates of Increased Alzheimer's-Related Cerebrovascular Disease in Adults with Down Syndrome

February 2022:

Tubulin Tyrosination Regulates Synaptic Function and is Disrupted in Alzheimer's Disease

Pyramidal Tract Neurons Drive Amplification of Excitatory Inputs to Striatum Through Cholinergic Interneurons

Associations Between Neuropsychiatric Symptoms and Neuropathological Diagnoses of Alzheimer Disease and Related Dementias

Longitudinal Associations Between Racial Discrimination and Hippocampal and White Matter Hyperintensity Volumes Among Older Black Adults

The Penalty of Stress - Epichaperomes Negatively Reshaping the Brain in Neurodegenerative Disorders

January 2022:

The National Institute on Aging Late-Onset Alzheimer's Disease Family Based Study: A Resource for Genetic Discovery

Atlas of RNA Editing Events Affecting Protein Expression in Aged and Alzheimer's Disease Human Brain Tissue

The Neuronal Retromer can Regulate Both Neuronal and Microglial Phenotypes of Alzheimer's Disease

Deep Learning Improves Utility of Tau PET in the Study of Alzheimer's Disease

December 2021:

Predictors of Incident Mild Cognitive Impairment and Its Course in a Diverse Community-Based Population

Atlas of RNA Editing Events Affecting Protein Expression in Aged and Alzheimer's Disease Human Brain Tissue

Integration of GWAS and Brain Transcriptomic Analyses in a Multiethnic Sample of 35,245 Older Adults Identifies DCDC2 Gene as Predictor of Episodic Memory Maintenance

November 2021:

KYNA/Ahr Signaling Suppresses Neural Stem Cell Plasticity and Neurogenesis in Adult Zebrafish Model of Alzheimer's Disease

Characterization of Mitochondrial DNA Quantity and Quality in the Human Aged and Alzheimer's Disease Brain

Self-Awareness for Financial Decision Making Abilities is Linked to Right Temporal Cortical Thickness in Older Adults

October 2021:

An Immune Response Characterizes Early Alzheimer's Disease Pathology and Subjective Cognitive Impairment in Hydrocephalus Biopsies

MEF2C Common Genetic Variation Is Associated With Different Aspects of Cognition in Non-Hispanic White and Caribbean Hispanic Non-demented Older Adults

Association of Regional White Matter Hyperintensities With Longitudinal Alzheimer-Like Pattern of Neurodegeneration in Older Adults

Age of Onset of Huntington's Disease in Carriers of Reduced Penetrance Alleles

September 2021:

Traversing the Aging Research and Health Equity Divide: Toward Intersectional Frameworks of Research Justice and Participation

Epigenomic Features Related to Microglia are Associated with Attenuated Effect of APOE ε4 on Alzheimer's Disease Risk in Humans

Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease

August 2021:

Neuropsychological Predictors of Severe Functional Dependency in a Multiethnic Community Cohort of Individuals with Alzheimer's Disease

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico

Effect of Aerobic Exercise on White Matter Tract Microstructure in Young and Middle-Aged Healthy Adults

July 2021:

Quantifying Age-Related Changes in Brain and Behavior: A Longitudinal Versus Cross-Sectional Approach

The Association Between Sex and Risk of Alzheimer's Disease in Adults with Down Syndrome

June 2021:

Marked Mild Cognitive Deficits in Humanized Mouse Model of Alzheimer's-Type Tau Pathology

Rapid ATF4 Depletion Resets Synaptic Responsiveness after cLTP

Polygenic Risk Score for Alzheimer's Disease in Caribbean Hispanics

Vascular-Derived SPARC and SerpinE1 Regulate Interneuron Tangential Migration and Accelerate Functional Maturation of Human Stem Cell-Derived Interneurons

May 2021:

PAC1 Receptor–Mediated Clearance of Tau in Postsynaptic Compartments Attenuates Tau Pathology in Mouse Brain

Socioeconomic and Psychosocial Mechanisms Underlying Racial/Ethnic Disparities in Cognition Among Older Adults

Recognition Memory and Divergent Cognitive Profiles in Prodromal Genetic Frontotemporal Dementia

April 2021:

Association Between Early Psychotic Symptoms and Alzheimer's Disease Prognosis in a Community-Based Cohort

Complexity and Graded Regulation of Neuronal Cell-Type-Specific Alternative Splicing Revealed by Single-Cell RNA Sequencing

The Microtubule Cytoskeleton at the Synapse & The Synaptic Life of Microtubules

Distinct Cortical Thickness Patterns Link Disparate Cerebral Cortex Regions to Select Mobility Domains

March 2021:

Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction

The AD Tau Core Spontaneously Self-Assembles and Recruits Full-Length Tau to Filaments

Olfactory Impairment is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease

Race/ethnicity and Gender Modify the Association Between Diet and Cognition in U.S. Older Adults: National Health and Nutrition Examination Survey 2011-2014

Insights Into the Role of Diet and Dietary Flavanols in Cognitive Aging: Results of a Randomized Controlled Trial

February 2021:

Plasma P-Tau181, P-Tau217, and Other Blood-Based Alzheimer's Disease Biomarkers in a Multi-Ethnic, Community Study

Pathogenic Role of Delta 2 Tubulin in Bortezomib-Induced Peripheral Neuropathy

CREB3L2-ATF4 Heterodimerization Defines a Transcriptional Hub of Alzheimer's Disease Gene Expression Linked to Neuropathology

Cláudio Gouveia Roque1, Kyung Min Chung1, Ethan P. McCurdy2, Radhika Jagannathan3, Lisa K. Randolph4, Krystal Herline-Killian1, Jimena Baleriola1,5,6,7, Ulrich Hengst1,8,*
1 The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
2 Integrated Program in Cellular, Molecular and Biomedical Studies, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
3 Division of Aging and Dementia, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
4 Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA.
5 Achucarro Basque Center for Neuroscience, Leioa, Spain.
6 IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
7 Department of Cell Biology and Histology, University of the Basque Country, Leioa, Spain.
8 Department of Pathology & Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.

Pictured from left to right: Best Poster Winner Cláudio Gouveia Roque, PhD with Ulrich Hengst, PhD (PI). Pictured from left to right: Best Poster Winner Cláudio Gouveia Roque, PhD with Ulrich Hengst, PhD (PI).

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with an increasing worldwide prevalence. The preclinical phase of AD, which can last 10-20 years, is characterized by the gradual accumulation of β-amyloid and tau aggregates in the brain, together with neuroinflammation and synaptic alterations. Several lines of evidence indicate that β-amyloid deposition precedes and accelerates tau pathology, the latter correlating with the onset of cognitive decline. Concurrently, gene expression changes across specific pathways tied to pathophysiology are observed, highlighting an important role for altered transcriptional regulators in AD. What causes these changes, how they interact with β-amyloid and tau pathologies, and whether they are drivers of disease or a response to it remain, however, unclear.

Here, we discover that β-amyloid promotes the formation of pathological CREB3L2–ATF4 transcription factor heterodimers in neurons. Through a multi-level approach based on AD datasets and a novel chemogenetic method that resolves the genomic binding profile of dimeric transcription factors (ChIPmera), we find that CREB3L2–ATF4 activates a transcription network that interacts with roughly half of the genes differentially expressed in AD, including subsets associated with β-amyloid and tau neuropathologies. CREB3L2–ATF4 activation drives tau hyperphosphorylation and secretion in neurons, in addition to misregulating the retromer, an endosomal complex linked to AD pathogenesis. We further provide evidence for increased heterodimer signaling in AD brain and identify dovitinib as a candidate molecule for normalizing β-amyloid-mediated transcriptional responses. The findings overall reveal differential transcription factor dimerization as a mechanism linking disease stimuli to the development of pathogenic cellular states.

Cláudio Gouveia Roque, PhD
Associate Research Scientist in the Taub Institute

Neuroproteasome Localization and Dysfunction Modulate Pathology in Alzheimer's Disease

Paradise V1,2, Sabu M1,2, Bafia J3, Sharif NA1,2, Nguyen C1,2, Dhanraj Mukim R1,2, Wang X1,2, Fu J4, Ndubisi J1,2, Maldonado G1,2, Strickland M5, Figueroa H1, Almeida D1,2, Hyman B6, Holtzman DM5, Nuriel T1, Ramachandran KV1,2,7
1 Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University
Vagelos College of Physicians and Surgeons, New York, NY 10032
Taub Institute for Research on Alzheimers Disease and the Aging Brain, Columbia University
Vagelos College of Physicians and Surgeons, New York, NY 10032
2 Department of Neurology, Columbia University Irving Medical Center. New York, NY 10032
3 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02139
4 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA
5 Department of Neurology, Developmental Biology, Hope Center for Neurological Disorders, Alzheimers Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110
6 Alzheimer Research Unit of the MassGeneral Institute for Neurodegenerative Disease, Department of Neurology of the Massachusetts General Hospital, and Harvard Medical School, Charlestown, Massachusetts 02129-4404
7 Department of Neuroscience, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032

Pictured from left to right: Kapil V. Ramachandran, PhD (PI) with Best Poster Winner Victoria E. Paradise. Pictured from left to right: Kapil V. Ramachandran, PhD (PI) with Best Poster Winner Victoria E. Paradise.

Following the discovery of a neuronal-specific plasma membrane-bound proteasome complex, or NMP, we endogenously tagged NMPs in vivo to reveal that NMPs co-purify with ApoE and Lrp1, defining a novel proteasomal degradation complex in neurons. We find that ApoE4 downregulates NMP localization relative to ApoE3 and ApoE2 in vitro, and in vivo in mouse and human and that NMP mislocalization is specific to regions that are selectively vulnerable in Alzheimer's Disease (AD). To evaluate the consequence of reduced NMP localization, we generated and leveraged chemical tools to selectively inhibit the NMP over the cytosolic proteasome and find that NMP inhibition causes pathological Tau aggregation in vitro and in vivo. We mechanistically link genetic risk factors for AD with protein aggregation through the neuroproteasome and reveal new principles of protein aggregation in neurons.

Victoria E. Paradise
Research Assistant

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