Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
January 2019

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December 2018:

» Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimer’s Human Brains

» 2: » Semantic Network Function Captured by Word Frequency in Nondemented APOE ε4 Carriers

November 2018:

» First Place: NSUN2 is Dysregulated in Alzheimer's Disease

» First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases

October 2018:

» #1 Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

» #2 An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

» #3 Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility

September 2018:

» #1 Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

» #2 Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE ε4 Haplotype Status: A Community-Based Cohort Study

August 2018:

» #1 A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research

» #2 An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

» #3 Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults

July 2018:

» #1 Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

» #2 Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease

June 2018:

» #1 Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

» #2 Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices

May 2018:

» #1 Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

» #2 Oligomeric Aβ1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons

April 2018:

» #1 Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

» #2 Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion

March 2018:

» #1 Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

» #2 White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes

February 2018:

» #1 ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

» #3 A Transcriptomic Atlas of Aged Human Microglia

January 2018:

» #1 Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

» #2 An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population

December 2017:

» #1 Neuronal Hyperactivity Due to Loss of Inhibitory Tone in APOE4 Mice Lacking Alzheimer's Disease-Like Pathology
» The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

» #2 The Historical Progression from ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia

November 2017:

» First Place: A CSF Proteomic Screen Links Retromer to Alzheimer's Pathogenic Pathways and Suggests Endosomal-Trafficking Biomarkers

» First Place: Microglia Identity in the Aged and AD Human Brain

October 2017:

» #1 Intra-Axonal Synthesis of SNAP25 is Required for the Formation of Presynaptic Terminals

» #2 Increased Localization of APP-C99 in Mitochondria-associated ER Membranes Causes Mitochondrial Dysfunction in Alzheimer Disease

September 2017:

» #1 Stabilization of Dynamic Microtubules by mDia1 Drives Tau-dependent Aβ1-42 Synaptotoxicity

» #2 An xQTL Map Integrates the Genetic Architecture of the Human Brain's Transcriptome and Epigenome

August 2017:

» #1 Abolishing Tau Cleavage by Caspases at Aspartate421 Causes Memory/Synaptic Plasticity Deficits and Pre-Pathological Tau Alterations

» #2 Mediterranean Diet and Cognitive Health: Initial Results from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD)

July 2017:

» #1 Abnormal Neurofilament Inclusions and Segregations in Dorsal Root Ganglia of A Charcot-Marie-Tooth Type 2E Mouse Model

» #2 LTP and Memory Impairment Caused by Extracellular Aβ and Tau Oligomers is APP-Dependent

June 2017:

» #1 Post translational Remodeling of Ryanodine Receptor Induces Calcium Leak Leading to Alzheimer's Disease like Pathologies and Cognitive Deficits

» #2 Neuropathologic Features of TOMM40 '523 Variant on Late-Life Cognitive Decline

May 2017:

» #1 Memory-Enhancing Effects of GEBR-32a, a New PDE4D Inhibitor Holding Promise for the Treatment of Alzheimer's Disease

» #2 An Approach to Studying the Neural Correlates of Reserve

April 2017:

» #1 Brain Atrophy Can Introduce Age-Related Differences in BOLD Response

» #2 Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities

March 2017:

» #1 Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes

» #2 Polygenic Risk Scores in Familial Alzheimer Diseases

February 2017:

» #1 Local Synthesis of Dynein Cofactors Matches Retrograde Transport to Acutely Changing Demands

» #2 Association of Obstructive Sleep Apnea with Episodic Memory and Cerebral Microvascular Pathology: A Preliminary Study

January 2017:

» #1 Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease

» #2 Novel Genetic Loci Underlying Human Intracranial Volume Identified Through Genome-Wide Association

» #3 Relation of Dysglycemia to Structural Brain Changes in a Multiethnic Elderly Cohort

Karen Duff, PhD

A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

As detailed in a recent Nature Neuroscience review by Drs. Karen Duff, Hongjun (Harry) Fu, and John Hardy (Institute of Neurology, London), understanding the molecular origins of selective neuronal vulnerability is of fundamental importance for all neurodegenerative diseases. Previous research by Dr. Duff and others has found that the distribution of neurons vulnerable to tauopathy follows a sequential pattern that suggests that cell populations in different regions of the brain are selectively at risk. More specifically, the morphology and location of cells within the entorhinal cortex (EC) and hippocampus that accumulate tau and degenerate in the earliest stages of Alzheimer's disease (AD) suggest that excitatory (EX) neurons are preferentially impacted. However, the exact molecular determinants underlying the selective vulnerability of EX neurons to tau pathology have not been established.

Figure 1: Co-expression network analysis of the subproteomes relevant to tau homeostasis.

Prompted by recent observations that age-related stress and dysfunction of protein homeostasis are observable in vulnerable neurons in aging and age-related neurodegenerative diseases, Drs. Duff and Fu (now at Ohio State), along with Dr. Michele Vendruscolo from the University of Cambridge, sought to explore these determinants by employing four complementary approaches that allowed the investigators to probe individual cells in mouse and human brain, as recently reported in Nature Neuroscience. First, using a series of cell-type-specific markers on AD patient brains and a mouse model of tauopathy previously generated by Dr. Duff’s laboratory, they showed that tau co-localizes predominantly with EX, compared to inhibitory (IN) neuron markers, not only in the EC but also in areas affected later in the disease, such as the neocortex. Second, using single-nucleus RNA-seq datasets from normal donors, they identified a substantial difference between EX and IN neurons in genes involved in a branch of the protein homeostasis system that modulates the aggregation and clearance of tau. Third, using the weighted gene co-expression network analysis, they identified that BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene in the co-expression network relevant to tau homeostasis. Lastly, they confirmed that BAG3 is differentially expressed in human EX and IN neurons in non-AD and AD brains and that it impacts tau accumulation in primary neurons.

Figure 2: Regional vulnerability in neurodegenerative diseases.

Taken together, these results support the conclusion that tau homeostasis contributes to the selective regional vulnerability of EX neurons to tau pathology and cell loss that defines AD, and suggest that dysregulation of specific branches of the protein homeostasis system plays an important role in the initiation and spread of tau pathology in AD and the primary tauopathies. A lay summary of these findings is currently available on CUIMC Newsroom.

Karen Duff, PhD
Deputy Director, Taub Institute
Professor of Pathology and Cell Biology (in Psychiatry and in the Taub Institute)

Eleanna Varangis, PhD

   Yaakov Stern, PhD

Hackeck, PhD
Christian Habeck, PhD   Qolamreza (Ray) Razlighi, PhD

Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain

Recent studies of the effect of aging on the brain have uncovered numerous ways in which brain structure and function change over the course of adulthood. In many cases, these age-related brain changes are linked to co-occurring cognitive changes, suggesting that different aspects of brain health may predict cognitive outcomes in the context of healthy aging. Recent studies in this field have turned to functional connectivity methodology to probe this relationship between brain function and cognitive outcomes, and have found support for the idea that inefficient patterns of functional connectivity between networks in the brain while at rest may underlie declining cognitive performance with aging. However, little is known about how network interactions during a cognitive task may be related to performance on that task, how different tasks may differentially affect the connectivity among networks in the brain, or how aging might play a role in these between-network interactions during a task.

Figure: All ages: connection x domain.

Together with Taub investigators Drs. Yaakov Stern, Christian Habeck, and Qolamreza (Ray) Razlighi, Dr. Eleanna Varangis examined connectivity among six cognitive networks during the performance of eleven different fMRI tasks stemming from four primary cognitive domains: Vocabulary, Processing Speed, Fluid Reasoning, and Episodic Memory. Participants were 142 healthy adults between the ages of 20-80. As published in the Journal of Cognitive Neuroscience, their study demonstrated that both participant age and cognitive task domain have independent effects on patterns of between-network connectivity. The results also showed that the strength of some of the connections between networks was related to task performance, with several of the relationships between task performance and connectivity varying by participant age.

These results provide support for the idea that older adults show different patterns of connectivity between cognitive networks while performing a cognitive task, and that some aspects of this connectivity may be related to cognitive performance. Further, this study is also the first to demonstrate differences in functional connectivity patterns during a cognitive task as a function of task domain, suggesting that the brain can dynamically reorganize itself to support a variety of cognitive functions throughout adulthood.

Eleanna Varangis, PhD
Postdoctoral Research Scientist (in the Gertrude H. Sergievsky Center)

Yaakov Stern, PhD
Professor of Neuropsychology (in Neurology, in Psychiatry, in the Gertrude H. Sergievsky Center, and in the Taub Institute)

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