Taub Institute: Genomics Core
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TaubCONNECT Research Perspective:
October 2022

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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

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

Grace Herod    Luke E. Berchowitz, PhD
Grace Herod, PhD    Luke E. Berchowitz, PhD

Amyloids arise from the repetitive addition of multiple copies of a protein with consequent conformational alterations. These fibrous assemblies are typically associated with the etiology of devastating age-related diseases such has Alzheimer’s disease and transthyretin amyloidosis. Recently, the paradigm that amyloids are intrinsically irreversible has been challenged by evidence indicating that some cells use reversible amyloid assemblies to carry out important functions. This means that healthy cells have evolved unknown mechanisms to dismantle these extremely stable structures which has vital implications for health and disease. In an effort led by graduate student Grace Herod (now Dr. Herod) in the Berchowitz lab, we sought to determine the mechanistic underpinning of cells’ remarkable capacity reverse and clear amyloids.

To address this question, we used a simple tractable model system: budding yeast gametes. During development, these cells use reversible amyloid-like assemblies of the RNA-binding protein Rim4 to repress translation of mRNAs that encode protein products that are harmful when prematurely expressed. Rim4 assemblies are termed ‘amyloid-like’ because they share a subset of the biochemical properties associated with disease-related amyloids such as resistance to ionic detergents and formation of stable cross-Β-sheet structures. Before this study, we knew that phosphorylation played a critical role in Rim4 clearance; a modification which also plays into the etiology of several disease-related amyloids. However, a mechanistic understanding of the contribution of phosphorylation to the clearance of amyloids and amyloid-like assemblies such as Rim4 clearance was lacking.

Graphical Abstract

In a paper published this year (2022) in Cell Reports, Grace found that Rim4 amyloid-like assemblies physically interact with a class of proteins called 14-3-3 proteins. This was exciting because many neurodegenerative disease-associated aggregates are bound by 14-3-3 proteins. Furthermore, 14-3-3 often act via their ability to bind phosphorylation modifications. She went on to demonstrate that the interaction between Rim4 and 14-3-3 proteins is critical for timely disassembly and clearance of Rim4. Grace’s results support a model by which 14-3-3 proteins play non-redundant roles in facilitating critical priming phosphorylation events on amyloid-like Rim4. Remarkably, Grace was able to expand the breadth of her findings by discovering that 14-3-3 proteins contribute to global protein aggregate homeostasis. Together, this study provides mechanistic model describing how 14-3-3 proteins may interact with phosphorylated residues to regulate and protect against disease-associated protein aggregates.

Luke E. Berchowitz, PhD
Assistant Professor of Genetics and Development (in the Taub Institute for Research on Alzheimer's Disease and-the Aging Brain)

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

Alexandra M. Gaynor, PhD
   Christian Habeck, PhD
Alexandra M. Gaynor, PhD

   Christian Habeck, PhD

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

Adherence to a Mediterranean diet (MeDi) has been associated with lower incidence of Alzheimer’s Disease (AD), lower risk of mild cognitive impairment (MCI), and slower cognitive decline in multiple domains. Relatively little research has investigated the relationship between diet and brain imaging biomarkers, but a small number of studies, including previous research from our group, have shown that MeDi adherence is associated with structural measures of brain health such as brain volume, cortical thickness, and structural connectivity. However, no prior research had examined the effects of MeDi on brain function as measured by fMRI. Meanwhile, work from our group has demonstrated that variability in cognitive performance during aging may depend on organization of functional brain networks, and increased internetwork resting-state functional connectivity (rsFC), which reflects less differentiation between functional networks, is associated with aging and poorer cognitive performance. Given evidence that MeDi impacts structural brain health, and that other lifestyle factors have been shown to moderate associations between brain measures and performance, it is possible that MeDi also plays a role in the relationship between rsFC and cognitive function.

Interaction between efects of MeDi group and overall rsFC on mean predicted fuid reasoning performance. Error bands refect 95% confdence intervals for mean predicted fuid reasoning for each MeDi
group. FLUID fuid reasoning performance, CI confdence interval.

Figure 1. Interaction between efects of MeDi group and overall rsFC on mean predicted fuid reasoning performance. Error bands refect 95% confdence intervals for mean predicted fuid reasoning for each MeDi group. FLUID fuid reasoning performance, CI confdence interval.

In a recent study, we tested whether MeDi moderates the associations between internetwork rsFC and cognitive performance. A sample of 201 cognitively intact adults 20–80 years old underwent resting state fMRI to measure rsFC among 10 networks, and completed 12 cognitive tasks assessing perceptual speed, fluid reasoning, episodic memory, and vocabulary. As published last month in Scientific Reports, we found that MeDi was not directly associated with rsFC, but significantly moderated the relationship between internetwork rsFC and fluid reasoning performance: in individuals with low adherence to MeDi, there was a significant negative association between overall internetwork rsFC and performance, but this effect was insignificant in those with moderate and high MeDi adherence.

Overall, our results suggest MeDi may support cognitive function by attenuating the negative effect of internetwork connectivity on cognitive function. Our findings could potentially be interpreted in the context of cognitive reserve (CR), the properties of the brain that allow for better than expected cognitive performance given the degree of injury- or age-related changes to the brain. Future research is warranted to understand how MeDi impacts structural and functional brain biomarkers and cognitive function over time, and to understand which precise patterns of nutrient intake may provide optimal protection against neurocognitive decline.

Alexandra M. Gaynor, PhD
Postdoctoral Research Scientist in the Taub Institute

Yian Gu, MD, MS, PhD
Assistant Professor of Neurological Sciences (in Neurology, Epidemiology in the Gertrude H. Sergievsky Center and the Taub Institute)

Allison Constant, PhD
   Lawrence S. Honig, MD, PhD
Allison Constant, MD

   Lawrence S. Honig, MD, PhD

Karen S. Marder, MD, MPH    Frank Provenzano, PhD
Karen S. Marder, MD, MPH   Frank Provenzano, PhD

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

Although Alzheimer’s Disease (AD) and Lewy Body Dementia (LBD) represent two different pathologies, they have substantial clinical overlap. In fact, of the spectrum of neurodegenerative disorders, AD and LBD are found to overlap most frequently, with up to 80-89% of patients diagnosed with LBD having some degree of AD pathology at autopsy. Evidence of the co-occurrence of these diseases can become especially difficult given that the have distinct neuropathological profile of beta-amyloid plaques, neurofibrillary tangles in AD and alpha-synuclein deposits in LBD. One common tool that has traditionally not shown promise in disambiguating LBD in the presence of AD is magnetic resonance imaging (MRI); however, previous studies have not capitalized on the longitudinal (changes of time) patterns of loss in AD and AD/LBD patients nor do they have confirmed neuropathology.

Figure 1
Figure 1. On the left table is the results of our linear mixed effects model analysis in AD vs LBD/AD showing atrophy over time for the three individual regions. On the right is a figure showing the three individual regions in an inflated left-brain hemisphere, Parahippocampal (green), cuneus (purple) and lateral occipital (blue).

In a study by the Provenzano lab recently published in Neurology, we sought to use a well-characterized longitudinal neuroimaging dataset of both AD and AD/LBD patients with confirmatory neuropathology to test if statistical models sensitive to longitudinal changes could distinguish LBD in patients with AD. Here, together with first author and Dean’s Research Fellow Dr. Allison Constant (P&S ‘22) and Drs. Karen Marder and Lawrence Honig, we sought to explore serial neuroimaging in 48 individuals with AD (n=24) and AD/LBD (n=24).

Anchoring this with neuropathological data from ADNI, we discovered that, when controlling for clinical disease severity among other factors, individuals with AD alone experienced higher rates of atrophy in the left cuneus, lateral occipital, and parahippocampal regions over time, when compared to patients with concomitant LBD using a linear mixed effect model analysis (p=0.22, 0.006 and 0.006 respectively). Furthermore, we found that the lattermost left cuneus volume positively correlated with Braak Lewy scores (Pearson product correlation 0.37, p=0.009) and left parahippocampal volume negatively correlated with Braak NFT score (-0.327, p=0.02), both neuropathological measures of disease burden. These findings suggest that longitudinal neuroimaging techniques may be useful in disambiguating disease progression trajectories in lieu of or in addition to other neuroimaging measures like PET scanning or dopamine sensitive SPECT scans.

Frank Provenzano, PhD
Assistant Professor of Neurological Sciences (in Neurology and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

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