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





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» #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




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


Ottavio Arancio, MD, PhD

Tau protein is the main component of neurofibrillary tangles that constitute one of the histological markers of Alzheimer's disease (AD). Recently, more attention has been focused on the cleavage of tau by caspases: a unique family of enzymes involved in programmed cell death that are known to play a role in the disease process associated with AD. In particular, caspases have been shown to cleave tau and form a fragment known as Delta-tau that has been suggested to be one of the main seeds for the formation of neurofibrillary tangles. This mechanism has been proposed as one of the early events occurring in AD brains, in response to the toxic modulation of beta-amyloid, another key protein in the disease. According to this scenario, Delta-tau favors tau aggregation in insoluble intracellular deposits.

The Taub Institute laboratory of Dr. Ottavio Arancio participated in a study, led by Dr. Luciano D'Adamio at Albert Einstein, aimed at elucidating the function of Delta-tau by generating a mouse model in which endogenous tau cannot be cleaved by caspases and, subsequently, cannot produce Delta-tau. Interestingly, when tested for memory, the mice exhibited a clear mnemonic deficit. This defect was corroborated by a deficit in synaptic plasticity while biochemical analyses detected increased levels of tau protein and phosphorylated tau in the brain.

Collectively, the data from this work, recently published online in Translational Psychiatry, suggests a new role for the site of cleavage of tau by caspases. Rather than being a pathogenic factor in AD, this cleavage may represent a negative feed-back mechanism to prevent formation of toxic tau species in neurons of cerebral areas essential for the cognitive functions compromised in AD patients.

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



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

Scarmeas, MD
Nikolaos Scarmeas, MD

Nutrition is a modifiable factor that has been consistently associated with cognition. Due to the complex biological interactions between different components of a diet, it has been proposed that the use of a whole-diet approach and the study of specific dietary patterns (rather than focusing on specific nutrients, foods or food ingredients) may provide advantages in understanding the role of diet in chronic diseases, including cognitive impairment in the elderly.

The Mediterranean Diet (MEDI) is such a dietary pattern and it is characterized by high intake of fish, vegetables, legumes, fruits, cereals, unsaturated fatty acids (mostly monounsaturated derived from olive oil), low intake of dairy products, meat, saturated fatty acids and a regular but moderate amount of ethanol (usually in the form of wine during meals). In 2006, Dr. Nikolaos Scarmeas and colleagues first demonstrated an association between higher MEDI adherence and lower dementia/AD/cognitive decline rates in the WHICAP population in Northern Manhattan. A similar, potentially protective role for the MEDI has been demonstrated by many cross-sectional and prospective epidemiological studies since, as well as one clinical trial and some meta-analyses.

Although it may seem incongruous, associations between adherence to the MEDI and cognitive performance have been only minimally studied in Mediterranean populations. Such studies are important, not only for external validity and generalization purposes but also because it is imperative to explore associations between cognition and truly higher levels of adherence to MEDI in countries where the prototypical form of the diet is followed.

The present study, recently published in PLOS ONE, provides a comprehensive analysis on the relationship between MEDI and its components, and detailed cognitive function (evaluated with methods similar to our WHICAP population) in a representative Greek population of aged adults, a population with an overall, life-long Mediterranean lifestyle. Among 1,865 individuals, aged 73±6 years, 90 were diagnosed with dementia and 223 with mild cognitive impairment. The odds for dementia was 65% lower for the individuals in the higher quartile of MEDI adherence, compared to those in the lowest one. Adherence to the MEDI was also associated with better performance in memory, language, visual-spatial and the composite score of cognitive domains, the associations being stronger for memory. Certain individual components of the MEDI (i.e. higher fish and non-refined cereal consumption) were also associated with lower dementia odds and better cognitive performance.

In summary, these findings suggest that MEDI in its a priori constructed prototype form may have cognitive benefits in traditional Mediterranean populations.

Nikolaos Scarmeas, MD
Associate Professor of Neurology (in the Taub Institute and Gertrude H. Sergievsky Center)
ns257@cumc.columbia.edu

 



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