Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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TaubCONNECT Research Perspectives:
March 2019



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February 2019:

» Effect of Aerobic Exercise on Cognition in Younger Adults: A Randomized Clinical Trial

» Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimer’s Models

January 2019:

» A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

» Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain

December 2018:

» Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimer’s Human Brains

» 2: » Semantic Network Function Captured by Word Frequency in Nondemented APOE ε4 Carriers

November 2018:

» First Place: NSUN2 is Dysregulated in Alzheimer's Disease

» First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases


October 2018:

» #1 Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

» #2 An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

» #3 Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility


September 2018:

» #1 Clinical Experience with Cerebrospinal Fluid Aβ42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

» #2 Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE ε4 Haplotype Status: A Community-Based Cohort Study


August 2018:

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

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

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


July 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


June 2018:

» #1 Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

» #2 Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices


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




Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of β-Amyloid Precursor Protein

Tae-Wan Kim, PhD

Familial Alzheimer’s disease (FAD)-associated presenilin 1 (PS1) serves as a catalytic subunit of γ-secretase complex, which mediates the proteolytic liberation of β-amyloid (Aβ) from β-amyloid precursor protein (APP). In addition to its proteolytic role, PS1 is involved in non-proteolytic functions such as protein trafficking and ion channel regulation. Furthermore, postmortem AD brains, as well as AD patients, have shown dysregulation of cholesterol metabolism. Since cholesterol has been implicated in regulating Aβ production, Taub faculty member Dr. Tae-Wan Kim, in collaboration with Dr. Sungkwon Chung and team from Sungkyunkwan University School of Medicine in South Korea, investigated whether the FAD PS1-associated cholesterol elevation could influence APP processing.

As recently published in PLOS ONE, they found that in Chinese hamster ovary (CHO) cells stably expressing FAD-associated PS1 ΔE9, total cholesterol levels are elevated compared to cells expressing wild-type PS1. They also found that localization of APP in cholesterol-enriched lipid rafts is substantially increased in the mutant cells. Reducing the cholesterol levels by either methyl-β-cyclodextrin or an inhibitor of CYP51, an enzyme mediating the elevated cholesterol in PS1 ΔE9-expressing cells, significantly reduced lipid raft-associated APP (see Fig. 4). In contrast, exogenous cholesterol increased lipid raft-associated APP. These data suggest that in the FAD PS1 ΔE9 cells, the elevated cellular cholesterol level contributes to the altered APP processing by increasing APP localized in lipid rafts. This is the first report demonstrating that elevated cholesterol owing to presenilin FAD could have functional impact on APP processing by modulating lipid raft localization of APP.

  Figure 4. Elevated cholesterol level in CHO PS1 ΔE9 cells was decreased by the inhibition of cholesterol biosynthesis. (a) CHO PS1 WT and ΔE9 cells were pre-treated with 1 μM tebuconazole for 48 h, and free cholesterol was visualized by filipin staining. (b) Filipin intensities were compared in the absence (control) and presence of tebuconazole (tebu). PS1 WT control (n = 14), PS1 WT with 10 μM tebuconazole (n = 11), ΔE9 control (n = 10), ΔE9 with 10 μM tebuconazole (n = 10). (c) CHO PS1 WT and ΔE9 cells were pre-treated with 0, 1, 5, or 10 μM tebuconazole for 48 h, and total cholesterol level was measured from cell membrane fractions using Amplex Red cholesterol assay kit (n = 8). One way ANOVA: **p<0.01, ***p<0.001.


Tae-Wan Kim, PhD
Associate Professor of Pathology and Cell Biology (in the Taub Institute)
twk16@cumc.columbia.edu



FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome

Edward D. Huey, MD   William Charles Kreisl, MD
Edward D. Huey, MD    William C. Kreisl, MD

The clinical diagnosis of corticobasal syndrome (CBS)—a disorder characterized by asymmetric parkinsonism, apraxia, cortical sensory deficits, and cognitive impairment—has been associated with different neuropathologic substrata, including corticobasal degeneration (CBS-CBD), Alzheimer disease (CBS-AD), and progressive supranuclear palsy (CBS-PSP). Clinical features are insufficient to identify the underlying pathologic substrate of CBS with certainty during life. 18Fluorodeoxy-glucose PET (FDG-PET) has been used to aid in CBS diagnosis, but the use of FDG-PET to try to differentiate the underlying pathologic substrata of CBS in vivo has not been extensively explored, even if available evidence suggests that different pathologies might show distinctive patterns of brain metabolism in CBS.


Figure 3: Regional hypometabolism compared to controls in the corticobasal syndrome (CBS)–corticobasal degeneration (CBD) (A), CBS–Alzheimer disease (B), and CBS–progressive supranuclear palsy (C) cohorts.(D) Conjunction analysis among the 3 groups. Statistical significance set at p < 0.05 family-wise error–corrected for multiple comparisons, except for C, where the threshold is p < 0.0001 uncorrected. Minimum cluster size: 100 voxels. The right side of the image represents the hemisphere contralateral to the more severely affected limbs. Significant clusters overlaid on a volumetric brain MRI template.

Thus, in collaboration with colleagues from multiple institutions, Taub faculty members Drs. Edward (Ted) Huey and William (Chuck) Kreisl co-authored a new study that systematically evaluated differences in topography of gray matter hypometabolism among different neuropathologic diagnoses underlying a CBS diagnosis, as assessed with FDG-PET and postmortem neuropathologic examination. As published in Neurology, they found that the primary pathology significantly affected the distribution of FDG-PET metabolism, with typical posterior temporoparietal or medial–frontal patterns observed in patients with CBS with a pathologic diagnosis of AD or PSP, respectively, and frontoparietal cortex, thalamus, and caudate nucleus in CBS-CBD. Their study demonstrates FDG-PET as an effective, complementary tool for proteinopathy identification in neurodegenerative diseases.

Edward D. Huey, MD
Associate Professor of Psychiatry and Neurology (in the Taub Institute)
edh2126@cumc.columbia.edu

William C. Kreisl, MD
Boris and Rose Katz Assistant Professor of Neurology (in the Taub Institute)
wck2107@cumc.columbia.edu



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