Taub Institute: Genomics Core
make an appointment

TaubCONNECT Research Perspectives:
February 2017

View Archive [close menu]

» #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

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

Ulrich Hengst, PhD    Joseph M. Villarin, PhD

Retrograde transport from axons to neuronal cell bodies is essential for neuronal development and function, and disruption of this process is associated with neurodevelopmental disorders and neurodegeneration. All microtubule-based retrograde transport in axons is mediated by a single motor, cytoplasmic dynein. An array of cofactors, regulators or cargo adaptors allows dynein to fulfill a multitude of functions and to transport many different cargos. How dynein-dependent transport is regulated by these proteins and how this process is controlled by the cell continues to be a very active field of research.

The unidirectional orientation of microtubules in axons necessitates that dynein is transported as an inactive cargo into the periphery, leading to the deceptively simple question that provoked the present study: how is the dynein motor activated and tuned for specific transport needs in distal axons? Published in Nature Communications, Taub faculty member Dr. Ulrich Hengst and members of his laboratory, along with first author and former graduate student Dr. Joseph Villarin, report that extracellular stimuli can activate the transport of specific cargos by triggering the local synthesis of those dynein regulators that are required for these specific cargos. NGF-induced transport of large cargos required local synthesis of Lis1 while smaller NGF-signaling endosomes required both Lis1 and the dynactin subunit p150Glued. Surprisingly, the removal of NGF also triggered local synthesis of Lis1, but in this context, it was required for the retrograde transport of a pro-apoptotic death signal. Villarin et al. further discovered that while NGF stimulation and deprivation both triggered Lis1 synthesis, they actually act on functionally distinct pools of axonally localized Lis1 transcripts that differ in their association with the RNA-binding protein APC.

Proposed model: NGF stimulation leads to the axonal translation of Dctn1 and APC-bound Pafah1b1. Locally synthesized Lis1 required for the retrograde transport of vesicular cargoes greater than 1 μm in diameter, and both axonally-derived Lis1 and p150Glued are necessary for the retrograde transport of NGF-signaling endosomes. NGF withdrawal has no effect on p150Glued synthesis but causes the production of Lis1 off not APC-bound Pafah1b1 transcripts. Lis1 produced in response to NGF withdrawal is required for the retrograde transport of a death signal (from: Villarin, J.M., McCurdy, E.P., Martínez, J.C., and Hengst, U. (2016). Local synthesis of dynein cofactors matches retrograde transport to acutely changing demands. Nat Commun 7, 13865)

The present study includes several conceptual advances for the understanding of intra-axonal transport. The tuning of the retrograde transport complex through the on-demand production of Lis1 or p150Glued provides a mechanistic explanation for how extracellular signals can acutely activate dynein and trigger the transport of different cargos in axons. They found that NGF deprivation triggered local Lis1 production that is required for the retrograde transport of a death signal. Dr. Hengst and colleagues described this finding as "exciting because it lends strong support for the dependence receptor hypothesis of TrkA receptor function. Rather than solely providing trophic support through the transport of NGF-signal endosomes from axons to cell bodies, our data suggest that NGF-binding to TrkA represses a cell intrinsic death signaling pathway downstream of TrkA, which we propose to be active GSK3β." Currently, it remains unknown how specificity in local translation is achieved. Only a certain set of localized mRNAs is translated in response to a specific stimulus, and many mRNAs react to more than one stimulus. Villarin et al. report that some Lis1 transcripts are axonally localized in an APC-dependent mode, making them responsive to NGF stimulation, while a second APC-independent pool of Lis1 is recruited into axons and locally translated only in NGF-starved axons. Their findings establish that the association with structural RNA-binding proteins such as can be a mechanism to establish functionally specialized pools of the same transcript species within axons.

In ongoing research, Dr. Hengst and colleagues are investigating whether similar mechanisms affect retrograde transport under neurodegenerative conditions, as part of a larger project to characterize the molecular mechanisms underlying the long-range spread of pathology in AD brain.

Ulrich Hengst, PhD
Associate Professor of Pathology and Cell Biology (in the Taub Institute)

Joseph M. Villarin, PhD
Student, Medical Scientist Training Program

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

Davangere P. Devanand, MBBS, MD    Nancy Kerner, MD

Obstructive sleep apnea (OSA) is a primary sleep disorder caused by repeated partial or complete upper airway collapse, despite an ongoing effort to breathe during sleep. Epidemiological studies report that individuals with OSA have a high prevalence of depression and cognitive impairment as compared to the general population. Current structural imaging data suggest that hippocampal atrophy and microvascular damage, including white matter hyperintensities, white matter integrity abnormalities, and gray matter loss, are accompanied by OSA. Although OSA is known for its destructive nature in the cerebral vascular and central neural systems, whether OSA plays an important role in the cognitive deteriorating process in older adults with amnestic mild cognitive impairment (aMCI) and depression is not clear. No prior study has evaluated the impact of OSA in this population.

In a sub-study of the Donepezil Treatment of Older Adults with Cognitive Impairment and Depression (DOTCODE) trial, led by Taub faculty members Drs. Davangere P. Devanand and Gregory Pelton, Dr. Nancy Kerner (an NIMH-funded T32 research fellow) and colleagues from the Division of Geriatric Psychiatry examined the association between OSA, cognition, and brain structural abnormalities in older adults with aMCI and depression. The investigators used the widely validated STOP-Bang questionnaire as an add-on instrument to assess the probability of OSA. Using standard methods, a score of 5 or greater was defined as a high probability of OSA (h-OSA), and a score of less than 5 was defined as a low probability of OSA (l-OSA). Baseline magnetic resonance imaging (MRI) was used to evaluate brain morphology. The initial 16 weeks of antidepressant treatment were part of the DOTCODE trial.

Figure 1. Comparison performance on delayed recall tasks following antidepressant treatment between high and low probability of obstructive sleep apnea. h-OSA: high probability of OSA (STOP-Bang score of 5 or higher); l-OSA: low probability of OSA (STOP-Bang score of 4 or less).

Kerner et al. reported their preliminary findings in the American Journal of Geriatric Psychiatry this month, which included 1) a significant association between OSA and severity of microvascular damage as identified on MRI, 2) no significant association between OSA and hippocampal or entorhinal cortex volume, even after controlling for intracranial volume, and 3) following 16 weeks of antidepressant treatment, no statistically significant changes in cognitive measures across multiple domains between the groups, with the exception of verbal episodic memory. One possible explanation for these findings is that OSA may facilitate additional neural injury (i.e., beyond that which is seen in AD pathology alone) and accelerate cognitive decline. Consequently, cognitive deficits accompanying OSA may persist or progress if OSA is left untreated.

Davangere P. Devanand, MD
Professor of Psychiatry (in Neurology and the Gertrude H. Sergievsky Center)

Nancy Kerner, MD
Instructor in Clinical Psychiatry


bottom bar