Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspective:
August 2024



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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




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

Yiyi Ma, MD, PhD   Richard Mayeux, MD, MSc    Badri Vardarajan, PhD, MS
Yiyi Ma, MD, PhD   Richard Mayeux, MD, MSc    Badri N. Vardarajan, PhD, MS

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder multiple etiologies. We studied both genetic variants and epigenetic features that contribute to the risk of AD by focusing our study on genetic variants that affect CpG sites (we called them CpGrelated single nucleotide polymorphisms (CGS)). CpG dinucleotides are a key part of epigenetic mechanisms in mammalian somatic cells. They are the only site in these cells where DNA methylation can occur, and they also harbor mutation hotspots. CpG sites are found in high frequency in genomic regions known as CpG islands, which are short DNA sequences with a high concentration of CpG and CG compared to the rest of the genome. In humans, about 70% of promoters near a gene's transcription start site contain a CpG island. CGSes or variants that affect CpG sites act as the hub of both the genetic and epigenetic effects because they alter the sequence of CpG dinucleotides which are the target site of DNA methylation.

Figure 1. Sliding CGS window search across the genome for the risk loci of clinical diagnosis of Alzheimer disease in Hispanics and non-Hispanic Whites. The genome-wide sliding window results for the Hispanics (upper panel in blue) and the non-Hispanic Whites (NHW) (lower panel in green) are shown in the miami plot. Each dot represents one 1-Kb window, and X and Y axis shows its genomic coordinate and -log10 transformed P value. The two horizontal red lines show the Bonferroni-corrected genome-wide significance threshold (P≤ 5×10-8) and those CGS windows passing the genome-wide significance threshold in either Hispanics or NHW are shown in red dots.

In our recently published study in Acta Neuropathologica, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 on Caribbean Hispanics (CH) CH and 1,283 Non-Hispanic Whites (NHW). Next, we evaluated the cis- and trans-effects of these associated CGSs on methylation and gene expression in the dorsolateral pre-frontal cortex in 179 CH brains. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score=55.19, P=4.06x10-8), the intergenic region between VRTN and SYNDIG1L (Score=-37.67, P=2.25x10-9), SPG7 (16q24.3) (Score=40.51, P=2.23x10-8), PVRL2 (Score=125.86, P=1.64x10-9), TOMM40 (Score=-18.58, P=4.61x10-8), and APOE (Score=75.12, P=7.26x10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in all the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P=0.08), brain methylation levels in all the other five loci affected downstream mRNA expression in CH (P<0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and synapse (FDR<0.05). DNA methylation at all the six loci and SYNDIG1 and TOMM40 gene expression were significantly associated with Braak stage In summary, we identified six CpG associated genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.

Yiyi Ma, MD, PhD
Assistant Professor of Neurological Sciences (in Neurology and in the Gertrude H. Sergievsky Center)
ym2666@cumc.columbia.edu

Badri N. Vardarajan, PhD, MS
Assistant Professor of Neurological Science (in Neurology, the Sergievsky Center, and the Taub Institute)
bnv2103@cumc.columbia.edu

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

Vilas Menon, PhD Osama Al-Dalahmah, MD, PhD
Vilas Menon, PhDOsama Al-Dalahmah, MD, PhD
 
Figure 1. Scatter plot showing genes with significant regression weights for CAG repeat length (y-axis). The order of genes on the x-axis is arbitrary. The color indicates the Benjamini–Hochberg adjusted p-value. Genes with coefficients two standard deviations above the mean are indicated.
Figure 1. Scatter plot showing genes with significant regression weights for CAG repeat length (y-axis). The order of genes on the x-axis is arbitrary. The color indicates the Benjamini–Hochberg adjusted p-value. Genes with coefficients two standard deviations above the mean are indicated.

Huntington’s disease (HD) is an incurable neurodegenerative disease caused by an expansion of CAG repeats in the HTT gene locus, leading to neuronal loss and astrogliosis. Despite the presence of the mutation in all brain cells, neuronal loss follows a classic distribution, the hallmark of which is severe degeneration of the striatum compared to cortical regions. Even within the striatum, the caudate nucleus shows more severe degeneration when compared to the nucleus accumbens, despite the relative similarity of the cell types that inhabit both regions. In the current study, now published in Nature Communications, we explored the role of astrocyte heterogeneity in the cell-type specific and regional vulnerability to neurodegeneration in HD. We used a combination of transcriptomic, lipidomic, and neuropathologic approaches to determine the relationships between specific astrocyte states and prototypic neurodegeneration patterns in HD.

Figure 2.
Figure 2. A) UMAP plot of astrocytes projected in isolation of other cell types, and color-coded by region. The bar plot on the top right shows the distribution of astrocytes between the three brain regions. B) Feature plots of normalized gene expression projected in the UMAP embeddings to highlight genes that differentiate fibrous-like (top) and protoplasmic astrocytes (bottom).

Combining bulk-level transcriptomics approaches with paired measurements of CAG repeat lengths allowed us to identify a set of genes that were increased as a function of CAG repeat length (Figure 1). These genes were enriched in glial and astrocytic genes and several pathways related to fatty acid metabolism – which is one of the primary functions of astrocytes. Indeed, lipidomic studies of cortical HD and control samples revealed several lipid species to be dysregulated in HD. Among the lipid species that increased in HD were long-chain polyunsaturated fatty acids, and we found them to be toxic to neurons in culture. Notably, astrocytes process polyunsaturated fatty acids, which further implicates astrocytes in HD pathology.

Motivated by these findings, we measured gene expression using single nucleus RNAseq from over 60 brain samples, including 20 HD and 10 controls across three brain regions: The cingulate cortex, the caudate nucleus, and the nucleus accumbens. We identified more than 45,000 astrocytes across the three brain regions (Figure 2A) and classified them as protoplasmic or CD44+ fibrous-like astrocytes (Figure 2B). HD caudate protoplasmic astrocytes showed higher enrichment of the gene signature correlated with CAG repeat length. Interestingly, we discovered that HD protoplasmic astrocytes in the cingulate cortex and nucleus accumbens, where neurodegeneration is less severe, showed high levels of metallothionein genes – which encode metal-sequestering anti-oxidative stress proteins. We confirmed these findings at the protein level in post-mortem human HD and control brain sections (Figure 3).

Figure 3. Immunofluorescent images
Figure 3. Immunofluorescent images of the caudate labeled for nuclei (DAPI-blue) and GFAP (green) to detect astrocytes (left panel), and MT3 (red-middle panel). A merge of the three channels is shown on the right. Arrows indicate DAPI, GFAP and MT3 positive cells (MT3 positive astrocytes) and arrowheads indicate MT3 negative astrocytes. Scale bar = 50 μm. Quantification of the percent of percent of astrocytes that were MT3 positive in the cingulate (Right). Unpaired one-tailed t-test with n = 8 for control and 6 for HD. Data are shown as mean ± SEM.

As we describe in our paper, astrocyte states were regionally heterogeneous. One state was characterized by elevated metallothionein protein expression, and was depleted from the caudate nucleus but enriched in less severely affected regions – the cingulate cortex and the nucleus accumbens. We sought to determine the impact of this astrocyte state on neuronal viability in collaboration with Dr. Andrew Yoo from Washington University in St. Louis, who developed a method to convert patient fibroblasts directly to striatal-type spiny projection neurons. We co-cultured astrocytes that upregulated one of the metallothionein proteins, MT3, or control astrocytes with HD patient-derived spiny striatal projection neurons. We found that compared to control astrocytes, neurons cocultured with MT3-astrocytes exhibited lower levels of markers of cell death, including Annexin V. We also confirmed the neuroprotective effect of MT3 astrocytes on neurons using another model of neurodegeneration in vitro. Thus, our findings indicate that the MT-high astrocyte state is compensatory or neuroprotective.

Altogether, our findings uncover heterogeneity of astrocyte states in the HD brain that correlates with the regional vulnerability to neurodegeneration. Further research is needed to causally connect astrocyte states to vulnerability to neurodegeneration. In addition to addressing this knowledge gap, we plan to explore the utility of compensatory astrocyte states as a therapeutic modality in HD, and in other neurodegenerative diseases.

Vilas Menon, PhD
Assistant Professor of Neurological Sciences (in Neurology and the Taub Institute)
vm2545@cumc.columbia.edu

Osama Al-Dalahmah, MD, PhD
Assistant Professor in Pathology and Cell Biology
oa2298@cumc.columbia.edu

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

Alexander A Sosunov, MD,PhD
   Guy M. McKhann II, MD
Alexander A Sosunov, MD,PhD
   Guy M. McKhann II, MD

Guomei Tang, PhD    James E.Goldman, MD, PhD
Guomei Tang, PhD   James E.Goldman, MD, PhD

Tuberous Sclerosis Complex (TSC) is a developmental disorder caused by mutations in the genes, TSC1 or TSC2, leading to a loss of function of the encoded proteins. These proteins normally inhibit the activation of a kinase, the mechanistic target of rapamycin complex 1 (mTORC1), and so the loss of these proteins will produce an abnormal activation of mTORC1. The disorder leads to the generation of collections of abnormal neurons and glia in the cortex, called “tubers”, as well as subventricular neoplasms, the so-called subependymal giant cell astrocytomas. Tubers are often the origins of seizures. In addition, many of the patients with TSC suffer from autistic spectrum disorders. One of the major cellular components of tubers are highly enlarged “cytomegalic” neurons, which develop from the pyramidal neurons of the isocortex.

Our group at Columbia published a paper in 2022 in Cell Reports, showing that in a mouse model in which Tsc1 is inactivated in late embryonic radial glial cells, the cytomegalic neurons receive enhanced excitatory input and contribute to cortical hyperexcitability and seizures. We also noticed that many of these cytomegalic neurons contained cytoplasmic vacuoles following chronic seizures. In a study recently published in Journal of Neuropathology and Experimental Neurology, Alexandre Sosunov, Guy McKhann II, Guomei Tang, and I further explored these vacuoles in the mouse model and in human tubers. The vacuole membranes contain plasma membrane components, including KCC2, the chloride channel that maintains a low intracellular chloride concentration so that GABA will produce synaptic inhibition. Many of these neurons show little KCC2 on the plasma membrane, suggesting that the intracellular chloride concentration may be increased. Our study proposes that the vacuoles arise from the Golgi network and represent a neuron’s inability to transfer Golgi membranes to the plasma membrane. 

Figure 1.  At the left is a vacuolated neuron from a human tuber. In the middle, a tuber neuron is filled with

vacuoles immunostained with an antibody against KCC2 (red), which outlines the vacuoles. At the right is the ultrastructure of a vacuole, single membrane bound, with invaginations of cytoplasm protruding into it.
Figure 1. At the left is a vacuolated neuron from a human tuber. In the middle, a tuber neuron is filled with vacuoles immunostained with an antibody against KCC2 (red), which outlines the vacuoles. At the right is the ultrastructure of a vacuole, single membrane bound, with invaginations of cytoplasm protruding into it.

Another feature of these abnormal neurons is that they are surrounded by peri-neuronal nets, a special organization of extracellular matrix, which is a normal feature of inhibitory neurons, but rarely present in excitatory cortical neurons. These nets may change the synaptic input of the neurons. We examined human tubers from autopsy and surgical excisions and found similar cytoplasmic vacuoles and peri-neuronal nets in the cytomegalic neurons. These pathological states of tuber neurons contribute to cortical hyperexcitability and seizure progression of individuals with TSC. How the abnormal activation of mTORC1 produces these abnormalities is not yet clear.

James E.Goldman, MD, PhD
Professor of Pathology and Cell Biology (in Psychiatry)
jeg5@cumc.columbia.edu

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

   
Angeliki Tsapanou, PhD    Yaakov Stern, PhD

The relationship between occupation and cognitive skills has been well researched; however, there is limited research on whether genetically predicted cognitive scores influence occupational choices. Given the significant role that occupation plays in an individual's life and well-being, identifying factors that may predispose cognitively healthy adults to certain occupations is crucial. In the current study, recently published in Behavior Genetics, we explored the association between the Cognitive Polygenic Index (PGI) and occupational choice in cognitively healthy adults aged 20-80 years.

Figure 1: Scatterplot for the association between Cog PGI and Data Occupational category, after adjustments for PCs, age, sex, and education (standardized predicted value). Lower Data value indicates higher complexity.
Figure 1. Scatterplot for the association between Cog PGI and Data Occupational category, after adjustments for PCs, age, sex, and education (standardized predicted value). Lower Data value indicates higher complexity.

Participants were drawn from two studies: the Reference Ability Neural Network (RANN) and the Cognitive Reserve (CR) study. Occupational complexity, measured across Data, People, and Things, was assessed using O*NET descriptors. Using a previously created Cognitive PGI and linear regression models, we analyzed 168 participants of white ethnicity, aged 20-80 years, with an average of 16 years of education. After controlling for factors such as age, sex, education, and principal components, we found a significant association between Cognitive PGI and the complexity of Data-related occupations. Higher Cognitive PGI was linked to higher Data complexity, while no significant associations were found for People or Things. Even after adjusting for brain morphometry measures like total cortical thickness and gray matter volume, the association with Data complexity remained significant (B=-0.059, SE: 0.029, p=0.045).

Our findings suggest that individuals with higher Cognitive PGI are more likely to pursue occupations with greater Data complexity, accounting for their brain morphometry. This suggests that genetic variation associated with cognition may predispose individuals for occupational choices.

Angeliki Tsapanou, PhD
Associate Research Scientist in the Gertrude H. Sergievsky Center
at2859@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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