Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
December 2019

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November 2019:

First Place: Studying Biochemical Mechanisms of Protective Gene Variants in Isogenic Stem Cell-derived Early Onset Alzheimerā€™s Disease Models

First Place: Glial Heterogeneity in Normal Human Cortex and Huntington Disease Interrogated Through Single Cell Nuclear RNA Sequencing

October 2019:

» Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

» Promotion of Axon Growth by the Secreted End of a Transcription Factor

September 2019:

» Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume

» Synaptic and Memory Dysfunction Induced by Tau Oligomers is Rescued by up-regulation of the Nitric Oxide Cascade

» Medicaid Contributes Substantial Costs to Dementia Care in an Ethnically Diverse Community Population

August 2019:

» Neuroinflammation in Frontotemporal Lobar Degeneration Revealed by 11Cā€PBR28 PET

» Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons

July 2019:

» Alzheimer's Association International Conference (AAIC 2019)

June 2019:

» #1 CpGā€Related SNPs in the MS4A Region Have a Doseā€Dependent Effect on Risk of Lateā€“Onset Alzheimer Disease

» #2 MFN2 Mutations in Charcotā€“Marieā€“Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics

May 2019:

» #1 Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease

» #2 Brain Biomarkers and Cognition Across Adulthood

April 2019:

» #1 Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers

» #2 Brain Arterial Dilatation and the Risk of Alzheimer's Disease

March 2019:

» #1 Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of Ī²-Amyloid Precursor Protein

» #2 FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome

February 2019:

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

» #2 Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimerā€™s Models

January 2019:

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

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

December 2018:

» #1 Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimerā€™s Human Brains

» #2 Semantic Network Function Captured by Word Frequency in Nondemented APOE Īµ4 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 AĪ²42, 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 Īµ4 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 AĪ²1-42 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

Activity-Dependent Nucleation of Dynamic Microtubules at Presynaptic Boutons Controls Neurotransmission

Francesca Bartolini, PhD
Xiaoyi (Lily) Qu, PhDFrancesca Bartolini, PhD

Dynamic microtubules (MTs) play a crucial role for rapid forms of axonal and dendritic transport and synaptic transmission. At postsynaptic sites, MT invasion into spines regulates spine morphology, motor and cargo pair transport into spines, and synaptic activity. MT dynamics and organization at presynaptic boutons remains largely unexplored, however, due to the limited size of most mammalian boutons and the poor resistance of dynamic microtubules to standard fixation procedures. Therefore, it remains unknown whether axonal de novo MT nucleation occurs post-development, is required for neurotransmission, and is a feature of neurons residing in an intact circuit.

de novo model Figure: Model of de novo nucleation of dynamic microtubules at en passant boutons. de novo nucleation of dynamic microtubules at excitatory boutons by Ī³-tubulin and the augmin complex provides tracks for interbouton delivery of a rate-limiting supply of synaptic vesicles. Knocking down of Ī³-tubulin abrogates de novo nucleated microtubules and interbouton synaptic vesicle transport, leading to defects in neurotransmitter release.

A new study by the laboratory of Dr. Francesca Bartolini, including first author Dr. Xiaoyi (Lily) Qu (now at Genentech), provides important insight into these questions with the surprising discovery that en passant presynaptic boutons of hippocampal neurons are hotspots for de novo nucleation of MTs, a function regulated by neuronal activity and rate-limiting for neurotransmission. Featured in the latest issue of Current Biology, with an accompanying editorial, they report that dynamic microtubules emerge at excitatory presynaptic boutons in vitro and ex vivo, as a result of restricted g-tubulin- and augmin-dependent de novo microtubule nucleation, with g-tubulin regulating the nucleation density, and augmin directing the uniform, plus-end directed growth towards the distal end of the axon. Importantly, Qu et al. found that de novo nucleation of dynamic microtubules is regulated by neuronal activity, required for bi-directional interbouton synaptic vesicle motility, and critical for synaptic vesicle exocytosis at sites of release.

These findings unveil a role for activity-dependent microtubule nucleation at en passant boutons in synaptic interbouton delivery that controls neurotransmission. Given the critical role that loss of a functional presynaptic machinery for MT nucleation may have for neurotransmission, it will be important to determine the in vivo significance of this selective MT nucleation, and whether dysregulation of this process can be associated with human neurological and neuropsychiatric illnesses caused by mutations in MT regulatory proteins residing presynaptically. Examples of such include tau in Alzheimerā€™s disease and other tauopathies, spastin in hereditary spastic paraplegias, and MAP1B and FMRP in Fragile X Syndrome.

Francesca Bartolini, PhD
Assistant Professor of Pathology & Cell Biology

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

Mercedes Arnes, PhD
   Ismael Santa-Maria Perez, PhD
Mercedes Arnes, PhD
   Ismael Santa-Maria Perez, PhD

Circadian rhythms impose daily cycles in a wide variety of behaviors and physiological processes. Alzheimerā€™s disease (AD) and related tauopathies are associated with a decay of circadian rhythms and the disruption of sleep patterns and cognitive function, but the mechanisms underlaying these alterations remain unclear. Traditional approaches in neurodegeneration research have focused on understanding how pathology impinges on circadian function. However, recent evidence demonstrates that circadian and sleep-wake cycle disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Since tau proteostasis is compromised in AD and related tauopathies, Dr. Ismael Santa-Maria and colleagues sought to understand the role tau protein plays in neuronal circadian biology and related behavior. Their findings were recently published in Frontiers in Aging Neuroscience.

tau deficiency
Figure 1. Effect of tau deficiency on daily rhythms of axonal structural remodeling.Ā (A)Ā Immunolabeling with anti-PDF and anti-CWO antibodies in LNv and DN neurons of adult brains from 7 day-old male flies. CWO immunostaining denotes the proper localization and morphology of DN neurons (arrow heads). Scale bar is 20 Ī¼m.Ā (B)Ā Scheme representing Sholl analysis in PDF-positive (black) LNv projections. Six concentric and evenly spaced (10 Ī¼m) rings (in red) are drawn. The centers of the rings are localized at the point where the first dorsal ramification starts in each hemisphere.Ā (C)Ā Representative confocal images of LNv neurons immunolabeled with anti-PDF antibody at ZT-2 and ZT-14, early morning and early evening, respectively. Panels show PDF-positive signal in LNv projections. Scale bar is 25 Ī¼m.Ā (D)Ā Plots representing Sholl analysis quantification at ZT2 and ZT14 for the corresponding genotypes. dTauā€“/ā€“Ā flies showed a significant reduction in the spreading across the concentric rings specifically at ZT-2, when compared to controls. No changes were found at ZT-14. Data represent mean and SEM analyzed by one-way ANOVA test, withĀ āˆ—āˆ—pĀ < 0.01 andĀ ****pĀ < 0.0001 or NS if no statistical significance (nĀ = 12ā€“14 hemispheres).

Dr Santa-Maria Lab Group
Santa-Maria Lab picture. Mercedes Arnes, first author on the right Joshua Cho, another contributing author on the left.
This project, led by first author and Postdoctoral Research Scientist Dr. Mercedes Arnes in the Santa-Maria Lab, provides strong evidence in vivo that tau has an impact on behavioral rhythms and sleep patterns. Circadian/sleep changes observed in tau knockout animals are accompanied by alterations in the structural and temporal dynamics of the terminal projections of the circadian pacemaker neurons. Tau levels change during the day in clock neurons, presumably fulfilling the cytoskeletal demands during periods of structural remodeling. However, it is unknown how tau levels are regulated in this context. As key regulators of mRNA stability and translation, microRNAs are implicated in multiple aspects of time keeping. The Santa-Maria Lab previously described the implication of miR-219 in the posttranscriptional regulation of tau and this microRNA has also been implicated in modulating the mammalian circadian-clock located in the suprachiasmatic nucleus.

Taken together, results by Arnes et al. suggest that loss of tau function participates in the regulation of circadian rhythms by modulating the correct operation and connectivity of core circadian networks and related behavior. The Santa-Maria lab will continue exploring mechanisms of tau regulation in clock neurons. Stay tuned!

Mercedes Arnes, PhD
Postdoctoral Research Scientist in the Department of Pathology and Cell Biology

Ismael Santa-Maria Perez, PhD
Assistant Professor of Pathology and Cell Biology

Sleep Fragmentation, Microglial Aging, and Cognitive Impairment in Adults with and Without Alzheimer's Dementia

Marta Olah, PhD
    Elizabeth M. Bradshaw, PhD
   Philip L. De Jager, MD, PhD
Marta Olah, PhD     Elizabeth M. Bradshaw, PhD
   Philip L. De Jager, MD, PhD

Sleep disruption may contribute to cognitive impairment and dementia in older adults. Sleep disruption has also been shown to result in gene expression changes characteristic of immune dysregulation, which in turn, might contribute to cognition-related disease processes, including Alzheimerā€™s disease (AD). Thus there is a possibility that sleep disruption may contribute to cognitive impairment through an immune mechanism. Microglia, the resident innate immune cells of the central nervous system, may play a key role in this. A role for microglia in AD has been implicated by genetic studies. Moreover, in rodents, chronic sleep restriction or deprivation can alter the immune signaling milieu in a way known to trigger changes in microglial function and can lead to morphologic microglial activation, and inhibiting this can improve cognition. However, data relating sleep, microglial biology, and cognition in humans are lackingā€”an important gap given differences in microglial biology between mice and humans.

Recently, a transcriptomic atlas of aged human microglia was established by Drs. Marta Olah, Elizabeth Bradshaw, and Philip L. De Jager from the Taub Institute and CTCN. In the present study, published recently in Science Advances, Olah and colleagues used this transcriptomic signature (coined the HuMi-Aged gene set) and the differentially expressed genes to disentangle the connection between microglia activation, aging, sleep fragmentation and cognitive decline. Working together with colleagues from multiple institutions, all datasets (actigraphy, cognitive assessment, cortical gene expression, AD pathology, microglia activation and microglia gene expression) originated from two prospective cohorts of aging and dementia at RUSH University: the Religious Orders Study and the Memory and Aging Project. In this cross-sectional study of older community-dwelling adults, they found that greater sleep fragmentation was associated with higher expression of genes characteristic of aged microglia and a greater density of morphologically activated microglia. As recently published in, the transcriptional changes were independent of chronological age, density of microglia, and dementia-related brain pathologies and were not completely accounted for by the increased density of morphologically activated microglia. Moreover, greater expression of genes characteristic of aged microglia was associated with worse cognition and partially accounted for the association between sleep fragmentation and worse cognition. These findings raise the possibility that microglial aging and activation may be a consequence of sleep fragmentation and may establish microglia as a link between sleep fragmentation and poor cognition in older adults.

Marta Olah, PhD
Assistant Professor of Neurological Sciences (in Neurology and the Taub Institute for Research on Alzheimerā€™s Disease and the Aging Brain)

Elizabeth M. Bradshaw, PhD
Adler Assistant Professor of Neurology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Institute for Genomic Medicine)

Philip L. De Jager, MD, PhD
Weil-Granat Professor of Neurology (in Neurology, the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Precision Medicine Initiative)

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