Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
August 2018





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June 2018:

» #1 Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

» #2 Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease


May 2018:

» #1 Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

» #2 Oligomeric Aβ1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons


April 2018:

» #1 Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

» #2 Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion


March 2018:

» #1 Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

» #2 White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes


February 2018:

» #1 ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

» #3 A Transcriptomic Atlas of Aged Human Microglia


January 2018:

» #1 Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

» #2 An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population


December 2017:

» #1 Neuronal Hyperactivity Due to Loss of Inhibitory Tone in APOE4 Mice Lacking Alzheimer's Disease-Like Pathology
and
» The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

» #2 The Historical Progression from ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia

November 2017:

» First Place: A CSF Proteomic Screen Links Retromer to Alzheimer's Pathogenic Pathways and Suggests Endosomal-Trafficking Biomarkers

» First Place: Microglia Identity in the Aged and AD Human Brain

October 2017:

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

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

September 2017:

» #1 Stabilization 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

August 2017:

» #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)

July 2017:

» #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

June 2017:

» #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

May 2017:

» #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

April 2017:

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

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

March 2017:

» #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

February 2017:

» #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

January 2017:

» #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




A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research


Philip De Jager, MD, PhD, MMSc

The Religious Order Study (ROS) and the Memory and Aging Project (MAP) are two prospective studies of aging that recruit older individuals without known dementia and include (1) detailed cognitive, neuroimaging and other ante-mortem phenotyping and (2) an autopsy at the time of death that includes a structured neuropathologic examination. They were designed to be used in joint analyses to maximize sample size, and for data and sample sharing, and are jointly referred to as "ROSMAP". Cataloguing multi-omic data in all of the ROSMAP subjects regardless of their disease trajectory can provide insight into the molecular events that contribute to aging-related cognitive decline. Taub faculty member Dr. Philip De Jager has been collaborating with the ROSMAP investigators over the past decade, and he has opened a new dimension to these important studies by generating large-scale molecular data from the brains of these subjects. These efforts started with the generation of genetic data and rapidly progressed to yield the most deeply characterized set of aging human brains.

A summary of these efforts was recently published in Scientific Data: Dr. De Jager and colleagues from Taub, along with Dr. David Bennett (Rush Alzheimer Disease Center) and others, report the creation of "A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research." This atlas was created from the systematic profiling of the dorsolateral prefrontal cortex obtained from a subset of autopsied individuals enrolled in ROSMAP. They include over 3,322 subjects. The present manuscript outlines the first generation of data, including genome-wide genotypes (n=2,090), whole genome sequencing (n=1,179), DNA methylation (n=740), chromatin immunoprecipitation with sequencing using an anti-Histone 3 Lysine 9 acetylation (H3K9Ac) antibody (n=712), RNA sequencing (n=638), and miRNA profile (n=702).

"The data described in this report represent data that exist today and are available to all investigators on Synapse," explains Dr. De Jager and colleagues. "Numerous additional layers of data, including proteomic and metabolomic data, from tissue samples and purified cell populations are being produced and will become available as the data are finalized. We look forward to this large set of molecular and phenotypic data being repurposed by the neuroscience and other communities of researchers."

Philip De Jager, MD, PhD, MMSc
Weil-Granat Professor of Neurology (in the Taub Institute, the Precision Medicine Initiative, and the Center for Translational and Computational Neuro-immunology)
pld2115@cumc.columbia.edu



An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

Yasir H. Qureshi, MD      
Yasir H. Qureshi, MD   Scott A. Small, MD    Christiane Reitz, MD, PhD

Lysosomal storage diseases (LSDs) are a group of inherited disorders that typically cause neurodegeneration early in life. Recent observations suggest that genetic variants that cause one type of LSD, Gaucher's disease, can act as a risk factor for developing Parkinson's disease. This observation also suggests that genes that cause other LSDs might act as risk factors for other late-onset neurodegenerative disorders, notably Alzheimer's disease (AD).


Figure: CLN5 colocalization with the late endosomal marker RAB7 and the ER maker Calnexin.

Published recently in Molecular and Cellular Biology, a new study by Drs. Scott Small and Christiane Reitz, with first author Dr. Yasir Qureshi and colleagues, focused on a select group of genes that cause neuronal ceroid lipofuscinosis (CLN3, CLN5, Cathepsin D) and have been directly or indirectly associated with retromer trafficking, which is also involved in the pathogenesis of late-onset AD. Capitalizing on whole exome sequencing data from multiplex AD families from the EFIGA Study, they identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD and caused glycosylation defects in the expressed protein, causing the protein to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5’s normal cellular location. They further showed that the AD-associated CLN5 variant reduced the normal processing of Cathepsin D and was associated with decreased levels of full-length APP, consistent with a defect in retromer-dependent trafficking.

Yasir H. Qureshi, MD
yhq2001@cumc.columbia.edu
Postdoctoral Research Scientist (in the Taub Institute)

Scott A. Small, MD
Boris and Rose Katz Professor of Neurology (in the Taub Institute, the Sergievsky Center, Radiology, and Psychiatry)
sas68@cumc.columbia.edu

Christiane Reitz, MD, PhD
Assistant Professor of Neurology and Epidemiology (in the Gertrude H. Sergievsky Center and the Taub Institute)
cr2101@cumc.columbia.edu



Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults


   
Jet M. J. Vonk, PhD   Adam M. Brickman, PhD

Verbal fluency tasks—naming as many items of a given criterion, typically letters or categories, under time constraints—are one of the cornerstones of the prevailing neuropsychological battery and, as such, are widely administered in both research and clinical settings. In general, letter fluency is more strongly linked to executive function abilities mediated by frontal brain regions, while category fluency relies more strongly on verbal abilities mediated by temporal regions. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individuals.

A new study by Dr. Adam Brickman, postdoctoral fellow and first author Dr. Jet Vonk from the laboratory of Dr. Jennifer Manly, and colleagues from Taub investigated the cortical structural correlates of letter and category fluency, including overlapping and different regions, in 505 individuals from the Washington Heights-Inwood Columbia Aging Project (WHICAP). As published recently in Cerebral Cortex, they found that the correlation between cortical thickness and verbal fluency in whole-brain analyses revealed distinct cortical signatures for letter fluency, primarily in frontal regions, and category fluency, in frontal and temporal-parietal regions. "By elucidating cortical signature of each fluency task," Vonk et al. conclude, "we can further build our understanding of the meaning of verbal fluency scores in various clinical populations and the theoretical mechanisms of executive functions and lexical processing."

Jet M. J. Vonk, PhD
Postdoctoral Research Scientist (in the Gertrude H. Sergievsky Center)
jv2528@cumc.columbia.edu

Adam M. Brickman, PhD
Associate Professor of Neuropsychology (in Neurology, the Taub Institute and the Gertrude H. Sergievsky Center)
amb2139@cumc.columbia.edu



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