Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
January 2017

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» #1 Unbiased Drug Screening Identified New Cellular Pathways that Regulate Apolipoprotein E Secretion in Human Primary Astrocytes

» #2 APrediction of Relapse After Discontinuation of Antipsychotic Treatment in Alzheimer's Disease: The Role of Hallucinations

» #1 Activating Transcription Factor 4 (ATF4) Modulates Rho GTPase Levels and Function via Regulation of RhoGDIα

» #2 Brain Regions Involved in Arousal and Reward Processing are Associated with Apathy in Alzheimer's Disease and Frontotemporal Dementia

» First Place: White Matter Changes in Alzheimer's Disease

» First Place: Understanding the Role of Phosphoinositide Dysregulation in Endolysosomal Dysfunction: Implications for Alzheimer's Disease

» #1 Time-Dependent Reversal of Synaptic Plasticity Induced by Physiological Concentrations of Oligomeric Aβ42: An Early Index of Alzheimer's Disease

» #2 Evidence that COMT Genotype and Proline Interact on Negative-Symptom Outcomes in Schizophrenia and Bipolar Disorder

» #1 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice

» #2 LRRK2 and RAB7L1 Coordinately Regulate Axonal Morphology and Lysosome Integrity in Diverse Cellular Contexts

» Alzheimer's Association International Conference (AAIC 2016)

» #1 Neuronal activity enhances tau propagation and tau pathology

» #2 Sleep Disordered Breathing and White Matter Hyperintensities in Community-Dwelling Elders

» #1 White Matter Integrity as a Mediator in the Relationship between Dietary Nutrients and Cognition in the Elderly

» #2 Dementia Risk and Protective Factors Differ in the Context of Memory Trajectory Groups

» #1 White Matter Hyperintensities are a Core Feature of Alzheimer's Disease: Evidence From the Dominantly Inherited Alzheimer Network

» #2 Parkinson's Disease: Guilt by Genetic Association

» #1 PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease

» #2 PP2A Methylation Controls Sensitivity and Resistance to β-Amyloid–Induced Cognitive and Electrophysiological Impairments

» #1 Tau-driven 26S Proteasome Impairment and Cognitive Dysfunction can be Prevented Early in Disease by Activating cAMP-PKA Signaling

» #2 Older Adults with Poor Self-rated Memory have less Depressive Symptoms and Better Memory Performance when Perceived Self-efficacy is High

» #1 Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory

» #2 Examining the Pathways Between Self-Awareness and Well-Being in Mild to Moderate Alzheimer Disease

» #3 Mediterranean Diet and Brain Structure in a Multiethnic Elderly Cohort

» #1 Progression of Extrapyramidal Signs in Alzheimer's Disease: Clinical and Neuropathological Correlates

» #2 Telomere Longitudinal Shortening as a Biomarker for Dementia Status of Adults With Down Syndrome

» #1 The Reference Ability Neural Network Study: Life-time stability of reference-ability neural networks derived from task maps of young adults

» #2 Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease

» #1 First Place: DREADDs Activation in the Medial Entorhinal Cortex (MEC) of EC-Tau Mice

» #1 First Place: Amyloid Precursor Protein (APP) is Ubiquitinated at Multiple Sites in the COOH-Terminal Domain as a Signal for Endosomal Sorting

» #1 F-box/LRR-repeat protein 7 is genetically associated with Alzheimer's disease

» #2 The keystone of Alzheimer pathogenesis might be sought in Aβ physiology

» #1 Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

» #2 Brain Amyloid Deposition and Longitudinal Cognitive Decline in Nondemented Older Subjects: Results from a Multi-Ethnic Population

» #1 Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome

» #2 Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease

» #1 SUMO1 Affects Synaptic Function, Spine Density and Memory

» #2 Connectivity and Circuitry in a Dish Versus in a Brain

» #1 Making Cognitive Latent Variables Manifest: Distinct Neural Networks For Fluid Reasoning And Processing Speed

» #2 Functional Network Mediates Age-related Differences in Reaction Time: a Replication and Extension Study

» #3 Self-Efficacy Buffers the Relationship between Educational Disadvantage and Executive Functioning

» #1 Specific Downregulation of Hippocampal ATF4 Reveals a Necessary Role in Synaptic Plasticity and Memory

» #2 Mediterranean Diet and Leukocyte Telomere Length in a Multi-ethnic Elderly Population

» #1 Cerebellum can serve as a pseudo-reference region in Alzheimer's disease to detect neuroinflammation measured with PET radioligand binding to translocator protein (TSPO)

» #2 Assembly and Interrogation of Alzheimer's Disease Genetic Networks Reveal Novel Regulators of Progression

» Neurotherapeutics: Rethinking Alzheimer's Disease Therapies

» #1 Dysregulation of microRNA-219 promotes neurodegeneration through post-transcriptional regulation of tau

» #2 Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community

» #3 Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar

» Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease

» Lobar Microbleeds Are Associated with a Decline in Executive Functioning in Older Adults

» Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

» Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease

» Coding mutations in SORL1 and Alzheimer's disease

» First Place: Pathogenic Role of Formin-mediated Stable Detyrosinated
     Microtubule Inductionby Amyloid beta

» First Place: Differential responsiveness to entorhinal cortical input distinguishes CA1 pyramidal neuron subpopulations

» Soluble amyloid beta levels are elevated in the white matter of Alzheimer's patients, independent of cortical plaque severity

» A Time Course Analysis of the Electrophysiological Properties of Neurons Differentiated from Human Induced Pluripotent Stem Cells (iPSCs)

» Axonally Synthesized ATF4 Transmits a Neurodegenerative Signal across Brain Regions

» Olfactory Dysfunction in the Elderly: Basic Circuitry and Alterations with Normal Aging and Alzheimer's Disease

» Neurological disorders: Quality-control pathway unlocked

» Estrogen Receptor β Variants Modify Risk for Alzheimer's Disease in a Multiethnic Female Cohort

» Combined suppression of CASP2 and CASP6 protects retinal ganglion cells from apoptosis and promotes axon regeneration through CNTF-mediated JAK/STAT signalling and Guidelines

» Local synthesis of TC10 is required for membrane expansion during axon outgrowth

» Dynamin 1 is Required for Memory Formation

» Behavioral Assays with Mouse Models of Alzheimer's Disease: Practical Considerations and Guidelines

» Biobanked Alzheimer's Brain Tissue Yields Living Neurons

» Picomolar Amyloid-ß Peptides Enhance Spontaneous Astrocyte Calcium Transients

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

S. Abid Hussaini, PhD

   Karen Duff, PhD

Hongjun (Harry) Fu, PhD    Gustavo Rodriguez, PhD

One of the earliest cognitive symptoms of Alzheimer's disease (AD) is confusion and disorientation in familiar surroundings. The entorhinal cortex (EC) is one of the regions in the brain known to store information of the space around us to create a 'cognitive map' and neurons of EC are among the first to be affected in AD. To understand how AD pathology leads to impaired spatial memory and cognitive map dysfunction, Drs. Karen Duff, Abid Hussaini, Hongjun (Harry) Fu, Gustavo Rodriguez, and colleagues from the Duff and Hussaini laboratories studied a mouse model (EC-Tau) which replicates the earliest stages of human Alzheimer's disease by forming Tau pathology in the EC that then spreads to the hippocampus and neocortex as the mice age.

Published this month in Neuron, the team found that the old (30+ month) EC-tau mice had significant difficulties navigating the Morris water maze and the T-maze compared to younger EC-tau mice with less pathology and controls. To investigate which neurons were involved in the observed spatial memory impairment, Drs. Hussaini and Rodriguez used in vivo electrophysiology to record neuronal activity in the EC as the mice explored an open field box. Extracellular electrophysiology recordings from the EC allowed them to evaluate the properties of excitatory as well
as inhibitory neurons.

Figure: GPS Fail. The grid cell firing pattern in a mouse with tau pathology in the entorhinal cortex (right) is weaker than in an age-matched control (left). [Courtesy of Abid Hussaini, Columbia University.]

Among the excitatory neurons, a specialized group of cells, called the grid cells, were affected. These recently discovered cells are like a coordinate or a map of the brain's GPS system and are known to be important for spatial memory. Normally, the grid cells fire uniformly across the entire space of the environment in a grid-like periodic pattern, but in the old EC-tau mice these cells fired less and the grid patterns were less periodic. Other excitatory cell types in the EC, including head-direction and border cells, were not affected. The inhibitory neurons had an opposite effect, firing a lot more in the old EC-tau mice than in the control group. These opposite effects changed the excitatory-inhibitory balance in the neuronal population of EC, most likely altering the overall network activity. This imbalance led to an increase in theta wave frequency which is known to be increased in human AD.

Detailed histopathological studies led by Dr. Harry Fu showed that tau pathology in the EC only formed in excitatory cells but not inhibitory cells, which were completely spared. Furthermore, overt tau pathology in the older mice was linked to extensive cell death, which only depleted the excitatory neurons but not inhibitory neurons.

These data suggest that deficits in spatial memory seen in early Alzheimer's disease can be caused by disruption of the brain's GPS system due to the selective vulnerability of excitatory neurons in the EC region of the brain. Tests of spatial memory, such as those being developed for smart-phone use by the elderly, might reveal impairment earlier than cognitive tests that are currently used. Results from this study by Fu et al. were also featured on ALZFORUM and CUMC Newsroom this month.

S. Abid Hussaini, PhD
Assistant Professor of Neurobiology (in Pathology and Cell Biology and the Taub Institute)

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

Hongjun (Harry) Fu, PhD
Associate Research Scientist (in the Taub Institute)

Gustavo Rodriguez, PhD
Postdoctoral Research Scientist (in the Taub Institute)

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

      Badri Vardarajan, PhD, MS
Sandra Barral, PhD    Adam M. Brickman, PhD    Badri N. Vardarajan, PhD, MS

Intracranial volume reflects the maximally attained brain size during development. It is closely related to brain volume in early life as the brain grows, but becomes stable after the brain has fully developed and remains unaffected by later age-related changes such as brain atrophy. It is a highly heritable trait, complemented by environmental factors, and identifying the underlying genes that influence variation in intracranial volume can contribute to our understanding of human brain development and related diseases. Yet, these genes have remained challenging to discover. Prior studies have identified only two influential genetic loci.

Drs. Sandra Barral, Adam Brickman, and Badri Vardarajan from the Taub Institute recently participated in a worldwide project of unprecedented scale, in which the largest-ever meta-analysis of a genome-wide association study (GWAS) of intracranial volume of 32,438 adults was performed. As published in Nature Neuroscience this month, five previously unknown genetic loci associated with intracranial volume were discovered and two known signals confirmed. According to the authors, the genes in these loci provide intriguing links between maximal brain size and various processes, including neural stem cell proliferation (FOXO3), neurodegeneration (MAPT), bone mineralization (CENPW), growth signaling (IGF1, HMGA2), DNA replication (GMNC) and rRNA maturation (PDCD). On a genome-wide scale, they discovered evidence of genetic correlation between intracranial volume and other key traits such as height and cognitive function, as well as with Parkinson's disease, indicating that the genes underlying brain development have far-reaching effects that extend well beyond the initial years of life. Their findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

For this study, Drs. Barral, Brickman, and Vardarajan directed the genetic and neuroimaging analysis of the Washington Heights-Inwood Community Aging Project (WHICAP) cohort, a community-based longitudinal study of aging and dementia among elderly, urban-dwelling residents led by Taub Co-Director Dr. Richard Mayeux since 1989. Drs. Barral and Vardarajan conducted genetic analysis to identify variants that influence intracranial volume using the genome-wide imputed genotyped data available. Their research integrates different statistical approaches (linkage analysis, case-control analysis, genome-wide association analysis, and whole exome/genome sequencing) to comprehensively characterize associations between genetic variants and neurological phenotypes, in studies of both normal aging and diseases of aging, such as Alzheimer’s disease. Dr. Brickman has been directing the acquisition and analysis of high-resolution magnetic resonance imaging (MRI) data from WHICAP. His laboratory primarily focuses on quantifying markers of neurodegeneration, normal brain integrity, and cerebrovascular disease, including measures of intracranial volume.

Sandra Barral, PhD
Assistant Professor of Neurogenetics (in Neurology, the Taub Institute, and Sergievsky Center)

Adam M. Brickman, PhD
Associate Professor of Neuropsychology (in Neurology, the Taub Institute, and Sergievsky Center)

Badri N. Vardarajan, PhD, MS
Assistant Professor of Bioinformatics (in Neurology and the Sergievsky Center)

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

Christiane Reitz, MD, PhD    Adam M. Brickman, PhD   Jose Luchsinger, MD

Dysglycemia is one of the most common public health problems in the United States. According to 2011 prevalence data from the Centers for Disease Control and Prevention (CDC), diabetes affects 25.8 million people in the United States, corresponding to 8.3% of the total U.S. population. Seventy-nine million persons (i.e. more than a quarter of the U.S. population) have pre-diabetes. This problem is more common in the elderly, the group also at highest risk for cognitive impairment. While there is evidence from epidemiological studies suggesting that dysglycemia is a risk factor for cognitive impairment, the underlying pathophysiological mechanisms remain unclear.

Published online in the Journal of the American Geriatrics Society, Drs. Christiane Reitz, Adam Brickman, Jose Luchsinger, and colleagues examined the relation of dysglycemia to brain structure and cognitive function in older adults in the Washington Heights-Inwood Community Aging Project (WHICAP) cohort. In this study, dysglycemia (diabetes, undiagnosed diabetes, and pre-diabetes) or higher HBA1c levels was associated with a higher number of brain infarcts, WMH volume and decreased total white matter, gray matter volumes and hippocampus volume in cross-sectional analyses, and a significant decline in gray matter volume in longitudinal analyses. In addition, dysglycemia was associated with lower performance in language, speed and visuospatial function, although these associations were attenuated when adjusting for education, APOE genotype, ethnic group, or vascular risk factors. These findings confirm that dysglycemia and diabetes affect cognition through both vascular and neurodegenerative pathways. Drs. Reitz, Brickman, and Luchsinger are conducting studies in humans and mice to further examine the mechanisms for these pathways.

Christiane Reitz, MD, PhD
Assistant Professor of Neurology and Epidemiology (in the Taub Institute and Sergievsky Center)

Adam M. Brickman, PhD
Associate Professor of Neuropsychology (in Neurology, the Taub Institute, and Sergievsky Center)

Jose Luchsinger, MD
Associate Professor of Medicine and Epidemiology (in the Taub Institute)


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