Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
October 2017

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» #1 Atabilization 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

» #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)

» #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

» #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

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

Ulrich Hengst, PhD    Andreia F. R. Batista    José C. Martínez

The formation of synapses is fundamental for the establishment of functional circuitry in the nervous system. Upon contact of axons with target-derived adhesive or soluble factors, presynaptic proteins cluster at the contact sites leading to the formation of presynaptic terminals. A new study by the laboratory of Ulrich Hengst, published in Cell Reports, sheds new light on a fundamental question in neurodevelopment: What is the source of the proteins from which the presynaptic terminals are built? In the current model, all proteins are transported from the cell body and rapidly recruited to sites of synaptic contact. First author Andreia Batista and José Martínez hypothesized that an alternative source for presynaptic proteins, intra-axonal synthesis, might be required as well.

The authors found that presynaptic organizing signals trigger local protein synthesis at their sites of contact with axons. The clustering of presynaptic proteins was prevented when protein synthesis inhibitors were applied specifically to axons. Previously, the transcript coding for the t-SNARE protein SNAP25 had been found in axonal transcriptome and translatome datasets. Here, the team of Dr. Hengst found that SNAP25 mRNA gets recruited to nascent presynaptic sites and locally translated. Axon-specific knockdown of SNAP25 mRNAs prevented the clustering of SNAP25 and other presynaptic proteins, and interfered with the release dynamics of synaptic vesicles. Together, these results establish that the induced intra-axonal synthesis of SNAP25 is a necessary, early step for the clustering of presynaptic proteins and the formation and function of presynapses.

Figure 1: Model for the role of local SNAP25 synthesis in synapse formation. Batista et al. find that during the assembly of presynaptic terminals, mRNA translation is upregulated at the nascent presynapses. Local SNAP25 synthesis is required for the proper formation of presynaptic terminals and synaptic vesicle release.

This process is probably not only important during the formation of synapses but also in the mature nervous system because SNAP25 continues to be produced at already established synapses. These results will be important for the understanding of SNAP25 regulation and, more generally, protein homeostasis at synapses. Ongoing research in the laboratory of Dr. Hengst investigates the role of local SNAP25 synthesis at mature synapses, and how this process is affected under pathological conditions such as Alzheimer’s disease.

Ulrich Hengst, PhD
Associate Professor of Pathology and Cell Biology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain

Andreia F. R. Batista
Graduate Student, MD/PhD program, Universidade do Minho, Portugal

José C. Martínez
Graduate Student, MD/PhD Program

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

Estela Area Gomez, PhD    Eric A. Schon, PhD

In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. The deleterious effects of Aβ deposition during the symptomatic stages of AD are undeniable, but the role of Aβ in earlier phases of the disease is still debated. During these early stages, AD cells exhibit alterations in numerous metabolic processes, such as perturbed mitochondrial function and loss of lipid homeostasis. These metabolic alterations occur early in AD, before the appearance of plaques, which has raised the possibility that other aspects of APP cleavage may be contributing to these metabolic changes. In this regard, increased levels of the C99 fragment have also been shown to contribute to AD pathogenesis.

The cleavage of C99 by γ-secretase activity occurs in specific areas of the ER called mitochondria-associated endoplasmic reticulum (ER) membranes (MAM). MAM is a lipid raft-like domain of the ER that regulates key cellular metabolic functions, such as lipid homeostasis and mitochondrial behavior. In a previous report, Drs. Estela Area Gomez and Eric Schon showed that ER-mitochondrial connectivity and MAM function are upregulated in AD.

Figure 1: Representative immunoelectron microscopy image of PS-DKO cells incubated with antibodies against APP-CTF conjugated with immunogold particles, showing retention of C99 in MAM areas of the ER.

In the present study, published in The EMBO Journal, they show that the γ-secretase substrate C99, in addition to its endosomal localization, is also present in MAM domains. Thus, both the γ-secretase enzyme activity (i.e. presenilins) and its direct substrate (i.e. C99) are located in the same compartment, where the former can cleave the latter. Moreover, chemical and genetic alterations of γ-secretase activity provoke a significant increase in the amount of this APP processing fragment in MAM regions. The increased presence of C99 in MAM causes the upregulation of MAM functionality (as measured by cholesterol esterification activity) and greater apposition between ER and mitochondria. In addition, the higher concentration of MAM-localized C99 induces the recruitment of sphingomyelinase to this ER domain and the subsequent deregulation of sphingolipid homeostasis, followed by higher levels of ceramide on mitochondria that impair respiratory chain activity.

These results support a model in which, in addition to Aβ, a critical component of AD pathogenesis is mediated by C99 toxicity through its effects on MAM and mitochondria.

Estela Area Gomez, PhD
Assistant Professor in the Department of Neurology

Eric A. Schon, PhD
Lewis P. Rowland Professor of Neurology (in Genetics and Development)


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