Taub Institute: Genomics Core
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TaubCONNECT Research Perspective:
November 2024



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October 2024:

Cellular Communities Reveal Trajectories of Brain Ageing and Alzheimer's Disease

Alzheimer's Disease CSF Biomarkers Correlate with Early Pathology and Alterations in Neuronal and Glial Gene Expression

A Cross-Disease Resource of Living Human Microglia Identifies Disease-Enriched Subsets and Tool Compounds Recapitulating Microglial States

August 2024:

Epigenetic and Genetic Risk of Alzheimer Disease from Autopsied Brains in two Ethnic Groups

Multi-Omic Analysis of Huntington's Disease Reveals a Compensatory Astrocyte State

Cytoplasmic Vacuolation and Ectopic Formation of Perineuronal Nets Are Characteristic Pathologies of Cytomegalic Neurons in Tuberous Sclerosis

Cognitive Polygenic Index Is Associated with Occupational Complexity Over and Above Brain Morphometry

July 2024:

Xenografted Human iPSC-Derived Neurons with the Familial Alzheimer's Disease APPV717I Mutation Reveal Dysregulated Transcriptome Signatures Linked to Synaptic Function and Implicate LINGO2 as a Disease Signaling Mediator

Extended Genome-Wide Association Study Employing the African Genome Resources Panel Identifies Novel Susceptibility Loci for Alzheimer's Disease in Individuals of African Ancestry

Adult-Onset Deactivation of Autophagy Leads to loss of Synapse Homeostasis and Cognitive Impairment, with Implications for Alzheimer Disease

June 2024:

ZCCHC17 Knockdown Phenocopies Alzheimer's Disease-Related Loss of Synaptic Proteins and Hyperexcitability

Design and Methods of the Early Age-Related Hearing Loss Investigation Randomized Controlled Trial

May 2024:

Updated Safety Results From Phase 3 Lecanemab Study in Early Alzheimer's Disease

The Broken Alzheimer's Disease Genome

Personality Traits and Cognitive Reserve—High Openness Benefits Cognition in the Presence of Age-Related Brain Changes

April 2024:

Rare Genetic Variation in Fibronectin 1 (FN1) Protects Against APOEε4 in Alzheimer's Disease

Cell Subtype-Specific Effects of Genetic Variation in the Alzheimer's Disease Brain

Osteopontin Drives Neuroinflammation and Cell Loss in MAPT-N279K Frontotemporal Dementia Patient Neurons

Childhood Engagement in Cognitively Stimulating Activities Moderates Relationships Between Brain Structure and Cognitive Function in Adulthood

March 2024:

Diet, Pace of Biological Aging, and Risk of Dementia in the Framingham Heart Study

The Matrix Receptor CD44 Is Present in Astrocytes throughout the Human Central Nervous System and Accumulates in Hypoxia and Seizures

Microglia Measured by TSPO PET are Associated with Alzheimer's Disease Pathology and Mediate key Steps in a Disease Progression Model

A Comparative Study of Structural Variant Calling in WGS from Alzheimer's Disease Families

February 2024:

Glucocorticoid Stress Hormones Stimulate Vesicle-Free Tau Secretion and Spreading in the Braint

Whole Genome-Wide Sequence Analysis of Long-Lived Families (Long-Life Family Study) Identifies MTUS2 Gene Associated with Late-Onset Alzheimer's Disease

In Vivo Tau is Associated with Change in Memory and Processing Speed, but not Reasoning, in Cognitively Unimpaired Older Adults

The Effects of Insufficient Sleep and Adequate Sleep on Cognitive Function in Healthy Adults

January 2024:

Risk of Alzheimer's Disease is Associated with Longitudinal Changes in Plasma Biomarkers in the Multi-Ethnic Washington Heights-Hamilton Heights-Inwood Columbia Aging Project (WHICAP) Cohort


ZCCHC17 Modulates Neuronal RNA Splicing and Supports Cognitive Resilience in Alzheimer's Disease


Benchmarking of Deep Neural Networks for Predicting Personal Gene Expression from DNA Sequence Highlights Shortcomings


TaubCONNECT Research Perspectives: Best Poster Presentations Taub Institute Retreat November 2023


December 2023:

Objective Physical Function in the Alzheimer's Disease Continuum: Association with Cerebrospinal Fluid Biomarkers in the ALBION Study

Racial/Ethnic Disparities in Misidentification of Dementia in Medicare Claims: Results from the Washington Heights-Inwood Columbia Aging Project

Neuropsychiatric Symptoms and Trajectories of Dependence and Cognition in a Sample of Community-Dwelling Older Adults with Dementia

Effects of Lithium on Serum Brain-Derived Neurotrophic Factor in Alzheimer's Patients with Agitation


November 2023:

2023 Taub Institute Grants for Emerging Research (TIGER) Awardees!


September 2023:

Rie1 and Sgn1 Form an RNA-Binding Complex that Enforces the Meiotic Entry Cell Fate Decision

Memory and Language Cognitive Data Harmonization Across the United States and Mexico

Education as a Moderator of Help Seeking Behavior in Subjective Cognitive Decline

August 2023:

Nerve Growth Factor Receptor (Ngfr) Induces Neurogenic Plasticity by Suppressing Reactive Astroglial Lcn2/Slc22a17 Signaling in Alzheimer's Disease

Multicellular Communities are Perturbed in the Aging Human Brain and Alzheimer's Disease

Simple Topological Task-based Functional Connectivity Features Predict Longitudinal Behavioral Change of Fluid Reasoning in the RANN Cohort

The Neuropathological Landscape of Hispanic and non-Hispanic White Decedents with Alzheimer Disease

July 2023:

Caspase-9 Inhibition Confers Stronger Neuronal and Vascular Protection Compared to VEGF Neutralization in a Mouse Model of Retinal Vein Occlusion

The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study Design and Methodology

Heart Failure-Induced Cognitive Dysfunction is Mediated by Intracellular Ca2+ Leak Through Ryanodine Receptor Type 2

June 2023:

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity

Dietary Flavanols Restore Hippocampal-Dependent Memory in Older Adults with Lower Diet Quality and Lower Habitual Flavanol Consumption

Survey of Neuroanatomic Sampling and Staining Procedures in Alzheimer Disease Research Center Brain Banks

May 2023:

Polygenic Risk Score Penetrance & Recurrence Risk in Familial Alzheimer Disease

Effects of Brain Maintenance and Cognitive Reserve on Age-related Decline in Three Cognitive Abilities

High School Quality is Associated with Cognition 58 Years Later

Older Adults Compensate for Switch, but not Mixing Costs, Relative to Younger Adults on an Intrinsically Cued Task Switching Experiment

April 2023:

Glucocorticoid-Driven Mitochondrial Damage Stimulates Tau Pathology

A Global View of the Genetic Basis of Alzheimer Disease

ARIA in Patients Treated with Lecanemab (BAN2401) in a Phase 2 Study in Early Alzheimer's Disease

March 2023:

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

Healthy Lifestyle Behaviors and Biological Aging in the US National Health and Nutrition Examination Surveys 1999-2018

February 2023:

Microglia Reactivity Entails Microtubule Remodeling from Acentrosomal to Centrosomal Arrays

Genuine Selective Caspase-2 Inhibition with new Irreversible Small Peptidomimetics

Costs During the Last Five Years of Life for Patients with Clinical and Pathological Confirmed Diagnosis of Lewy Body Dementia and Alzheimer's Disease


January 2023:

Histopathology of the Cerebellar Cortex in Essential Rremor and Other Neurodegenerative Motor Disorders: Comparative Analysis of 320 Brains

The Caribbean-Hispanic Alzheimer's Disease Brain Transcriptome Reveals Ancestry-Specific Disease Mechanisms

Comparison of Amyloid Burden in Individuals with Down Syndrome Versus Autosomal Dominant Alzheimer's Disease: A Cross-Sectional Study

Neuronal Membrane Proteasomes Regulate Neuronal Circuit Activity in Vivo and are Required for Learning-Induced Behavioral Plasticity

December 2022:

A Systemic Cell Stress Signal Confers Neuronal Resilience Toward Oxidative Stress in a Hedgehog-Dependent Manner

RNA Methyltransferase NSun2 Deficiency Promotes Neurodegeneration through Epitranscriptomic Regulation of Tau Phosphorylation

Cell Type-Specific Changes Identified by Single-Cell Transcriptomics in Alzheimer's Disease

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample

November 2022:

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

First Place: Neuroproteasome Localization and Dysfunction Modulate Pathology in Alzheimer's Disease

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




ABCA7-Dependent Induction of Neuropeptide Y is Required for Synaptic Resilience in Alzheimer’s Disease Through BDNF/NGFR Signaling

HĂĽseyin Tayran   Elanur Yilmaz, PhD    Prabesh Bhattarai, PhD
HĂĽseyin Tayran   Elanur Yilmaz, PhD    Prabesh Bhattarai, PhD
Richard Mayeux, MD, MSc   Caghan Kizil, PhD     
Richard Mayeux, MD, MSc   Caghan Kizil, PhD   

In our recent publication in Cell Genomics, we explored the critical role of the ABCA7 gene in mediating synaptic resilience through the regulation of neuropeptide Y (NPY) in Alzheimer’s disease (AD). Using a multidisciplinary approach, including a CRISPR-Cas9-mediated zebrafish model, patient-derived iPSCs, transcriptomics, and clinical patient data, we identified a mechanism how ABCA7 regulates brain resilience in Alzheimer's disease. Our zebrafish model of amyloid-beta (Aβ) toxicity revealed that ABCA7 is indispensable for maintaining and inducing the expression of Neuropeptide Y, which plays a pivotal role in the brain’s resilience against AD pathology. Single-cell transcriptomics demonstrated that the loss of ABCA7 disrupts the NPY–BDNF–NGFR signaling axis, leading to reduced synaptic density, impaired astroglial proliferation, and a compromised resilience response. These findings were corroborated in patient-derived iPSCs, where ABCA7 knockout resulted in diminished NPY expression under Aβ-induced stress.

Graphical Abstract
Graphical Abstract

A central finding of our work is the bidirectional relationship between NPY and BDNF. We showed that reduced NPY levels in ABCA7-deficient zebrafish and human neurons resulted in downstream suppression of BDNF expression, a neurotrophic factor essential for synaptic maintenance and neural plasticity. Rescue experiments demonstrated that ectopic NPY administration restored synaptic density and BDNF levels, emphasizing NPY's upstream regulatory role. As highlighted in the CUIMC Newsroom, clinical data from human cohorts confirmed the translational relevance of these findings. Reduced NPY levels in AD patients strongly correlated with advanced Braak stages, while epigenetic analyses linked ABCA7 variants to altered methylation patterns in NPY and BDNF promoters. This interplay underscores ABCA7's role in modulating epigenetic and transcriptional networks that govern brain resilience.

Our study also identified NGFR as a mediator of BDNF signaling in astroglia, a finding with significant implications for neurogenesis. In the zebrafish model, NGFR expression was tightly linked to astroglial proliferation, a process disrupted by ABCA7 loss. These insights align with our previous work demonstrating that NGFR activation in mammalian models enhances neurogenesis and mitigates AD pathology.

These findings position the ABCA7–NPY–BDNF–NGFR axis as a central mechanism underlying synaptic resilience and offer a promising therapeutic target. By leveraging NPY and BDNF signaling pathways, future interventions could amplify the brain's natural protective responses to AD-related pathology. This study exemplifies the power of integrative approaches, combining cross-species models with human-derived data, to unravel complex neurodegenerative mechanisms. By advancing our understanding of ABCA7's role in synaptic and cellular resilience, we contribute toward designing targeted therapies aimed at mitigating AD progression.

Caghan Kizil, PhD
Associate Professor of Neurological Sciences (in Neurology and in the Taub Institute)
ck2893@cumc.columbia.edu

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Regulation of Synapse Density by Pumilio RNA-Binding Proteins

Lisa Randolph, PhD Ulrich Hengst, PhD
Lisa Randolph, PhDUlrich Hengst, PhD

Neurons are among the most morphologically complex, dynamic, and long-lived cells in the human body, leading to special challenges for the spatial and temporal control of gene expression. All aspects of neuronal development and function crucially depend on post-transcriptional mechanism for the control of gene expression, and essentially all these mechanisms involve the function of RNA-binding proteins (RBPs) that control among others a transcript’s splicing, localization, translation, and stability. Coordinated RNA regulation is crucial for example for axon growth and pathfinding, and at later developmental stages for synapse formation and stabilization.

Previously, we had identified that elevated expression levels of mammalian RNA-binding proteins Pumilio 2 (Pum2) during early developmental stages retained mRNAs, including transcripts encoding synaptic proteins within the cell body, thereby preventing their localization and translation in axons and dendrites. Given that Pum2 and its homologue Pum1 are developmentally downregulated around the time of synapse formation, we hypothesized that reduced expressions of Pum2 and potentially Pum1 would constitute an endogenous mechanism for the precise timing of synapse formation.

Figure: Pumilio RNA-binding proteins exhibit developmental downregulation in the brain.
Figure: Pumilio RNA-binding proteins exhibit developmental downregulation in the brain. Decreased expression of Pum1/2 facilitates synapse maturation and enhances the density of excitatory and inhibitory synapses. The regulation of Pumilio levels constitutes an intrinsic cellular mechanism for modulating synapse formation.

In our recently published Cell Reports study, Dr. Lisa Randolph, then a graduate student in the Neurobiology and Behavior Program at Columbia University, tested this hypothesis by prematurely suppressing the expression of Pum1 and 2 in cultured hippocampal and cortical neurons. Indeed, simultaneous knockdown of the Pumilios resulted in significantly increased synapse density. Contrary to our expectations, the augmentation in synapse numbers was not attributable to earlier synapse formation but rather to enhanced maturation of newly formed synapses. In accordance with a potential function in controlling protein synthesis in the neuronal periphery, we detected elevated protein synthesis at synaptic sites upon Pum1/2 knockdown.

We propose a mechanism whereby Pumilio proteins repress the local synthesis of synaptic proteins, such as SNAP-25, thereby curbing the capacity of neurons to form and maintain synapses. Notably, this regulatory mechanism is operative not only during development but also after the majority of synapses have already been formed, as knockdown of Pum1/2 at later times still elicited exuberant synapse formation. Our findings have potential implications for future studies related to normal aging, as Pum2 is upregulated in late life, and its hyperactivity has been associated with an aging phenotype in model organisms.

Ulrich Hengst, PhD
Professor of Pathology and Cell Biology (in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain)
uh2112@cumc.columbia.edu

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CD33 and SHP-1/PTPN6 Interaction in Alzheimer's Disease

Mamunur Rashid, PhD
   Annie J. Lee, PhD
Mamunur Rashid, PhD

   Annie J. Lee, PhD

Badri N. Vardarajan, PhD, MS    Elizabeth M. Bradshaw, PhD
Badri N. Vardarajan, PhD, MS   Elizabeth M. Bradshaw, PhD
 
Figure: CD33 and SHP-1 interact in situ in a CD33 genotype-dependent manner.
Figure: CD33 and SHP-1 interact in situ in a CD33 genotype-dependent manner. (A) A representative confocal image of post-mortem human prefrontal cortex stained for proximity ligation assays (PLA). The proximity ligation puncta (red dots, zoomed in inset) represent the protein–protein interaction between CD33 and SHP-1. DAPI (blue) is used to counterstain the nucleus. (B) Quantification of the PLA dots show a significant increase in the PLA counts in the CD33 CC group (n = 16 tissue sections, 11.36 ± 1.956) when compared to the CD33 AA groups (n = 10 tissue sections, 0.6185 ± 0.1482). Data represented as the mean ± SEM. *** p < 0.001, unpaired t-test. Scale bar: 100 μm; 10 μm inset.

CD33, a transmembrane glycoprotein expressed on myeloid cells, plays a crucial role in regulating immune responses through its inhibitory signaling motifs. Genetic variations in CD33, such as the rs3865444C risk allele, have been associated with Alzheimer’s disease (AD) susceptibility, influencing amyloid β clearance and contributing to plaque accumulation. SHP-1 (encoded by PTPN6) is a protein tyrosine phosphatase that binds to CD33’s ITIM motifs, modulating signaling pathways critical to microglial function. Understanding the interaction between CD33 and SHP-1 is essential for determining their role in AD pathophysiology and their potential as therapeutic targets.

As recently published in Genes, in collaboration with Dr. David Bennett (Rush University), we examined the critical interaction between CD33 and SHP-1 in the context of AD-associated genetic variation. We explored how genetic variations at the CD33 locus influence its binding with SHP-1, a key protein tyrosine phosphatase, using the proximity ligation technique in human microglia and microglia-like cells. Our findings demonstrate a genotype and activation state-dependent interaction between CD33 and SHP-1, which may contribute to the increased AD risk linked to certain CD33 variants. Moreover, we revealed that the interaction between CD33 and PTPN6 (SHP-1) significantly associates with AD-related pathological traits, while interactions with PTPN11 (SHP-2), a related protein tyrosine phosphatase that also binds CD33, do not show similar effects. These results emphasize the role of innate immune mechanisms in AD susceptibility and suggest new avenues for therapeutic interventions targeting these pathways.

Elizabeth M. Bradshaw, PhD
Adler Assistant Professor of Neurological Sciences (in Neurology and the Taub Institute)
Co-Director, The Carol and Gene Ludwig Center for Research on Neurodegeneration
emb2280@cumc.columbia.edu

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A Neural Implementation of Cognitive Reserve: Insights from a Longitudinal fMRI Study of Set-Switching in Aging

Fatemeh Hasanzadeh, PhD
   Christian Habeck, PhD
Fatemeh Hasanzadeh, PhD

   Christian Habeck, PhD

Yunglin Gazes PhD    Yaakov Stern, PhD
Yunglin Gazes, PhD   Yaakov Stern, PhD

In this longitudinal study spanning five years, we investigated how task-related neural activation during an experimental task-switching paradigm serves as a neural marker of cognitive reserve (CR). Specifically, our team, including postdoctoral scientist Dr. Fatemeh Hasanzadeh, as well as Drs. Christian Habeck and Yunglin Gazes, examined whether greater engagement of functional brain networks during an executive control function task could buffer cognitive performance against age-related structural brain changes that typically impair cognition.

In this executive task, participants see one letter at a time on the screen and must make a decision about it using a button press. If the letter is red, they make an lower/upper case decision; green letters require a vowel/consonant decision. In the “single-task” condition, only one color is presented throughout, and participants make the same decision for every letter. In the “dual-task,” the color of the letters changes throughout the trial and the participant must switch their response based on that color. "Switch cost" is the added time and reduced accuracy associated with dual- vs single-task.

We applied ordinal trend canonical variates analysis (OrT CVA) to functional MRI (fMRI) data from single and dual-task conditions. This advanced multivariate technique identified brain regions showing consistent activation changes as task difficulty increased from the single to dual task, characterizing individual differences in neural responses to task-switching demands. Concurrently, we constructed a multivariate measure of brain structure—combining cortical and subcortical volume and thickness changes—through elastic net regression, summarizing the structural brain changes that were associated with decline in task performance over 5 years.


Figure: Areas of the brain that show concomitant increased (red) and decreased (blue) activation when switching from single to dual conditions. Participants who exhibited a greater utilization of this pattern at baseline showed greater resilience, and could lessen the effect of reduced brain reserve on cognitive performance.

Our results, recently published in the Neurobiology of Aging, revealed that the degree of differential activation between single and dual conditions observed at the initial visit moderated the relationship between structural brain changes and cognitive decline. Individuals with greater task-related activation exhibited a reduced impact of structural brain decline on switch cost, supporting the cognitive reserve theory that CR is a “property of the brain” that enables resilience against aging-related brain changes.

By moving beyond traditional CR proxies like IQ and education, this study provides direct evidence that differential functional activation can represent a neural implementation of CR. The findings highlight the critical role of differential utilization of a brain network in preserving cognitive flexibility, offering new insights into the mechanisms underlying cognitive reserve and healthy aging.

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

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