Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
July 2017





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» #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

» #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

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

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

» #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

» #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

» #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

» #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




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

      
Ronald K. H. Liem, PhD    Jian Zhao, PhD    Kristy R. Brown

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy that affects 1:2500 people worldwide. Patients suffer from degeneration of the peripheral nerves that control sensory information of the foot/leg and hand/arm. Although over 90 causative genes have been identified, most do not yet have good animal models to investigate mechanisms of disease onset and progression. The scarcity of clinically relevant animal models is also hampering the development of treatments for the disease. The laboratory of Taub faculty member Dr. Ronald Liem has focused on CMT2E, which is caused by mutations in the neurofilament light gene, NEFL. A number of different dominant mutations in this gene can cause CMT2E. The Liem laboratory has made a knock-in mouse model containing the N98S mutation in Nefl. These NeflN98S/+ mutant mice reproduce many of the early-onset symptoms that have been described in patients with the N98S mutation, including problems in balance, tremor, cerebellar abnormalities, hearing defects and accumulations of neurofilamentous inclusions in spinal cord neurons. Most of these symptoms can already be observed in two week old mice. Studying this animal model is, therefore, of key importance to understand the mechanism and identify therapeutic targets.


Figure 1. Immunofluorescence micrographs of cultured DRG neurons from Nefl+/+ and NeflN98S/+ mice labeling NFL.
(A and C) Low power views of DRG neurons from Nefl+/+ (A) and NeflN98S/+ (C) mice. Note that in NeflN98S/+ DRG neurons, the processes are characterized by large amounts of enlarged and bright particles along the processes, pointed by arrows (C). Scale bars = 50 μm

A study by Zhao et al. recently published in PLOS One conducted ultrastructural and immunofluorescence studies of dorsal root ganglia (DRG) from NeflN98S/+ mutant mice. Neurofilamentous inclusions were readily observed in cultures of adult DRG neurons stained with an antibody to the neurofilament light protein (Fig.1). Similarly, abnormal neurofilamentous inclusions were described in embryonic day 15 DRG cultures from the mutant animals. Electron microscopic analysis showed that these inclusions are made up of disordered neurofilaments packed in high density, segregated from other organelles. Immunochemical studies show decreased NFL protein levels in DRG, cerebellum and spinal cord in NeflN98S/+ mice, and total NFL protein pool is shifted toward the triton-insoluble fraction. These inclusions are believed to play an important role in affecting normal trafficking and function in peripheral neurons. This EM study reveals the nature of the inclusions in NeflN98S/+ mice. These results provide useful information to understand mechanisms of CMT2E disease, and identify DRG from NeflN98S/+ mice as a useful cell line model for therapeutic testing.

In summary, this study reveals the nature of inclusions in NeflN98S/+ mutant mice, and provides useful information in explaining how mutations in a cytoskeleton protein lead to neurodegeneration. More importantly, these studies establish a potential therapeutic approach to identify effective compounds to treat CMT diseases.

Ronald K. H. Liem, PhD
Professor of Pathology and Cell Biology (in the Taub Institute)
rkl2@cumc.columbia.edu

Jian Zhao, PhD
Associate Research Scientist, Department of Pathology and Cell Biology
jz2554@cumc.columbia.edu

Kristy R. Brown
Senior Staff Associate
krb1@cumc.columbia.edu



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


Ottavio Arancio, MD, PhD

The amyloid cascade hypothesis has dominated research on the origin of Alzheimer's disease (AD) over the last 20 years. According to the hypothesis, the protein beta-amyloid starts the disease by triggering pathology of another protein called tau, which then spreads the disease throughout the brain independently of beta-amyloid. The two proteins would, therefore, be placed in series, and this has been blamed for the failure of the many clinical trials attempting to cure the disease by interfering with beta-amyloid without blocking the negative effects of the downstream tau. This view is challenged in a recent work by Taub faculty member Dr. Ottavio Arancio, leading an international team of researchers, including the laboratories of Daniela Puzzo and Claudio Grassi at the University of Catania and the Catholic University of Rome in Italy, and the laboratories of Paul Fraser at the University of Toronto in Canada and Luciano D'Adamio at Albert Einstein in New York.

Starting from the discovery that a brief exposure to small soluble forms of beta-amyloid and tau, alone or in combination, dramatically disrupts memory and cell to cell communication, the team has found that beta-amyloid and tau, but not other proteins involved in other neurodegenerative diseases, require the presence of amyloid precursor protein (APP) to disrupt memory and cell to cell communication. Intriguingly, they also found that APP is necessary for the entrance of the two proteins within cells. Indeed, suppression of APP rescued the deleterious effects of both soluble beta-amyloid and tau on memory and cell to cell communication.

Thus, after this manuscript, the story about the origin of this devastating disorder needs to be told in a different manner. Beta-amyloid and tau are no longer placed in series as the amyloid cascade posits; instead, they should be placed in parallel in a series of negative events that could be initiated by the two proteins separately or in combination. Intriguingly, APP is at a key central point in the disease origin. The consequences of such a new sequence of events is that it is unlikely that therapies aimed at blocking the negative effects of beta-amyloid and tau alone will work. Most importantly, the research from the Arancio laboratory indicates that the field should look at APP as a target for therapies against Alzheimer's disease.

Ottavio Arancio, MD, PhD
Professor of Pathology and Cell Biology (in the Taub Institute)
oa1@cumc.columbia.edu

 



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