Taub Institute: Genomics Core
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TaubCONNECT Research Perspective:
February 2023

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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

Francesca Bartolini, PhD

Microglia Reactivity Entails Microtubule Remodeling from Acentrosomal to Centrosomal Arrays

Microglia cells are a specialized cell type that acts as a “sentinel” in our brain and plays critical roles in neuroinflammatory and neurodegenerative disease. Activating signaling triggers a change in microglia morphology that reflects a highly activated state associated with phagocytosis and proinflammatory function. The intracellular mechanisms driving microglia transition from the homeostatic to a reactive state are however poorly understood. This is partially due to challenges in imaging purified microglia without perturbing their homeostatic or reactive state.

Graphical Abstract
Graphical Abstract. Microglia cell transition between homeostatic and reactive states is characterized by a dramatic reorganization of the microtubule cytoskeleton from a Golgi outpost-nucleated acentrosomal array to a pericentrosomal radial array to enable proper cytokine release.

In this manuscript, through in vitro phenotyping and in vivo validation, the Bartolini laboratory, together with collaborators from “Sapienza” University and the Institute of Technology in Italy, reports the break-through discovery that reactive microglia undergo a dramatic reorganization of their microtubule cytoskeleton, the most abundant cytoskeleton in the brain. As recently published in Cell Reports, we found that reactive microglia engage a unique example of microtubule transition from an array of parallel microtubules nucleated at Golgi-outposts to a radial array in which all the microtubules are anchored to a pericentrosomal region. Our findings suggest that this reorganization is critical for supporting the microglia “patrolling” and proinflammatory function, providing a novel target for reducing microglia reactivity in inflammatory and neurodegenerative disease. Given the role for spinal microglia in the remission and recurrence of neuropathic pain, this study may also pave the way to determine the contribution of microglial microtubule dysfunction in the etiology of neuropathic pain caused by chemotherapeutic drugs, most of which target the microtubule cytoskeleton.

These spearheading observations will set the ground to visualize microtubule remodeling as a dynamic marker of microglia activation, and to examine the impact of microtubule targeting drugs on microglia reactivity in neurodegenerative disease and microglia-mediated regulation of synaptic function.

Francesca Bartolini, PhD
Associate Professor of Pathology and Cell Biology at CUIMC

Genuine Selective Caspase-2 Inhibition with new Irreversible Small Peptidomimetics

Andrew Sproul, PhD   Carol M. Troy, MD, PhD   
Andrew A. Sproul, PhD    Carol M. Troy, MD, PhD    Michael Shelanski, MD, PhD

Caspases are a family of cell death proteases that have been associated with neurodegenerative disorders since their initial identification. Broad-spectrum caspase inhibitors were proposed as possible neurodegenerative therapeutics, but significant toxicity occurs when such inhibitors are used for longer than 2 weeks, and the need for specific inhibitors targeting only the relevant caspase(s) was identified more than a decade ago. Most caspase inhibitors have been designed to target the active sites of each caspase based on combinatorial libraries. However, the active sites are highly similar across caspases, and the tetra- and pentapeptides used to target individual caspases have failed to distinguish between caspases. Most caspase inhibitors marketed as specific have been found to be non-specific at the functional level, providing data about caspases in general, not about specific caspases. Additionally, the interpretation of data obtained using these inhibitors has been complicated because some caspases have non-apoptotic functions that benefit the brain, such as regulating neurogenesis and synaptic activity. Therefore, prior studies using agents that target multiple caspases may have manipulated pathways beyond apoptosis, confounding interpretations of whether caspase inhibition is associated with therapeutic benefits.

Figure 7. LJ2a and LJ3a prevent dendritic spine loss induced by Aβ oligomers in hippocampal primary cultures.
Figure 7. LJ2a and LJ3a prevent dendritic spine loss induced by Aβ oligomers in hippocampal primary cultures. Swiss mice hippocampal neurons (E18) were cultured for 3 weeks in microfluidic chambers (20,000 neurons/chamber). Then neurons were pre-treated, or not, for 1 h with the indicated concentration of LJ2a or LJ3a, and treated for 6 h with 100 nM of monomeric Aβ (Aβ mono) or 100 nM of Aβ1-42 oligomers ([Aβ]n) then fixed and permeabilized for (immuno)staining with anti-MAP2, Phalloidin, anti-actin F, and anti-Bassoon. Microfluidic chambers were analyzed by fluorescence microscopy by counting phalloidin clusters affixed to MAP2 and Bassoon on hippocampal dendrites. a Representative micrograph of triple stained dendrites after 6 h in the presence (lower panel, [Aβ]n) or absence (upper panel, Co.) of Aβ oligomers. b, c. Quantification of dendritic spines in hippocampal neurons treated with LJ2a (b) or LJ3a (c) as indicated. Both inhibitors show synaptoprotective effects at submicromolar concentration. Histograms represent means (±SD) of 3 independent experiments (****p value ‹0.0001).

Studies from Taub labs and others have implicated caspase-2 as a key modulator of pathology in Alzheimer’s Disease (AD). We have shown that genetic knockdown or knockout provides protection against synaptic loss and neurodegeneration in mouse models of AD. While genetic approaches provide proof-of-concept we also want to develop tools for inhibiting caspase-2 activity that could potentially be developed as therapeutics. In a study recently published in Cell Death & Disease, in collaboration with Etienne Jacotot of Inserm (formerly a Schaefer fellow at Columbia), and Taub colleagues Drs. Michael Shelanski and Andrew Sproul, we have characterized new peptidomimetics, harboring non-natural modifications at the P2 position and an irreversible warhead (shown to be safe in humans). Enzyme kinetics show that these new compounds, such as LJ2 or its specific isomers LJ2a, and LJ3a, strongly and irreversibly inhibit caspase-2 with genuine selectivity. Particularly, LJ3a is highly selective for caspase-2 (946 times less efficient on caspase-3), far above previously described caspase-2 inhibitors. Additional enzyme kinetics experiments with human recombinant caspase-1, caspase-6, cathepsin-B, cathepsin-L, cathepsin-D, thrombin, plasmin, trypsin, kallikrein-1, -6, and -8 indicate that LJ2a and LJ3a have very limited or no effect on these enzymes. We further show that these potent and selective caspase-2 inhibitors have strong effects in several biological models, including protection against cell death induced by microtubule destabilization, and inhibition of synapse loss in primary hippocampal neurons treated with β-amyloid oligomers where submicromolar concentrations of LJ2a and of LJ3a prevent synapse loss, indicating a potential for further investigations in AD treatment.

Carol M. Troy, MD, PhD
Professor of Pathology and Cell Biology and Neurology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at CUIMC

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

Yian Gu, MD, MS, PhD    Stephanie Cosentino, PhD    Yaakov Stern, PhD
Yian Gu, MD, MS, PhD    Stephanie Cosentino, PhD    Yaakov Stern, PhD

Dementia with Lewy bodies (DLB) is the second most common form of dementia following Alzheimer’s disease (AD). Several studies have reported a higher estimated cost of care associated with DLB compared to AD, yet our understanding of healthcare utilization and costs in DLB continues to be limited. While administrative databases are a rich source of information on healthcare use and costs, issues related to the substantial under-diagnosis, missed diagnosis, or mis-diagnosis of DLB, AD, and other dementias pose significant challenges when analyses rely solely on claims data. Additionally, though pathological confirmation is a gold standard of disease diagnosis, the question of whether clinical diagnosis and pathology-confirmed diagnosis are associated with healthcare costs has yet to be examined.

Figure 2. Unadjusted cumulative Medicare A + B Payment, last 5 years of life, by pathology confirmed diagnosis. Medicare expenditures data were obtained from Medicare Standard Analytic Files (SAFs) and included all covered services (inpatient, outpatient, professional, emergency department, physician office visits, hospital outpatient visits, hospice, skilled nursing facility, home health, and durable medical supplies) in 6-month intervals from date of death to 5 years prior to death. Expenditures were adjusted to 2021$ using the medical care component of the Consumer Price Index.

Figure 2

To explore some of these gaps, our latest work, co-authored by Taub colleagues Drs. Yian Gu and Stephanie Cosentino, represents the first known study to examine cost of care in autopsy confirmed DLB patients. Here, in collaboration with lead author Dr. Carolyn Zhu (Mount Sinai; not pictured), we analyzed healthcare expenditures in the last 5 years of life in a cohort of patients from the Predictors 2 study that had been clinically diagnosed with AD or DLB and had autopsy confirmed diagnosis of pure-AD, pure-DLB, or AD+DLB. As recently reported in the Journal of Alzheimer’s Disease, without considering the underlying pathology, we found that patients clinically diagnosed with DLB had higher expenditures than those clinically diagnosed with AD. When we looked at pathology, we found that expenditures were substantially higher in patients with mixed AD+LB pathology compared to those with pure-AD and pure-DLB pathologies. A closer look at the interaction between clinical and pathologic diagnoses showed that expenditures were particularly high in patients with mixed AD+LB pathologies, especially in those clinically diagnosed with DLB.

Our results point to the gaps in our understanding of healthcare costs in DLB and highlight the importance of having both clinical and pathology diagnoses in examining healthcare costs. With the high prevalence of DLB in an aging population and extremely high societal burden of healthcare costs, it is critical to improve current understanding of costs of care among patients with DLB in order to inform public policies and clinical decision-making, as this will ultimately improve the quality of patient care.

Yaakov Stern, PhD
Florence Irving Professor of Neuropsychology (in Neurology, Psychiatry, the Sergievsky Center, and the Taub Institute)

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