Taub Institute: Genomics Core
AN NIA-FUNDED ALZHEIMER'S DISEASE RESEARCH CENTER
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8th ANNUAL TAUB INSTITUTE RESEARCH RETREAT
November 2017


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» In the Lab: Frank Provenzano, PhD

» Clinical Research: James M. Noble, MD, MS

» Ronald K. H. Liem, PhD

» Natura Myeku, PhD

» Christiane Reitz, MD, PhD

» Quantitative Neuroimaging Laboratory: Qolamreza R. Razlighi, PhD

» In the Lab: Nicole Schupf, PhD

» In the Lab: Sandra Barral Rodriguez, PhD

» In the Lab: Wai Haung Yu, PhD

» In the Lab: Giuseppe Tosto, MD, PhD

» In the Lab: Catherine L. Clelland, MS, PhD

» 7th ANNUAL TAUB RETREAT, October 2016

» In the Lab: Andrew A. Sproul, PhD

» In the Lab: William C. Kreisl, MD

» In the Lab: Badri N. Vardarajan, PhD, MS

» In the Lab: Diego E. Berman, PhD

» In the Lab: Joseph H. Lee, DrPH

» Dr. Yaakov Stern on the Concept of Cognitive Reserve

» The Alzheimer's Disease Research Center at Columbia University Celebrates 25 Years

» In the Lab: Stephanie Cosentino, PhD

» Clinical Research: Edward D. Huey, MD

» In the Lab: Jennifer J. Manly, PhD

» Clinical Research: Lawrence S. Honig, MD, PhD, FAAN

» 6th ANNUAL TAUB RETREAT, October 2015

» In the Lab: Andrew Teich, MD, PhD

» In the Lab: Ismael Santa-Maria Perez, PhD

» In the Lab: Christian Habeck, PhD

» In the Lab: Roger Lefort, PhD

» In the Lab: Clarissa Waites, PhD

» In the Lab: Francesca Bartolini, PhD

» In the Lab: Tae-Wan Kim, PhD

» In the Lab: Carol M. Troy, MD, PhD

» In the Lab: Adam M. Brickman

» In the Lab: Gil Di Paolo

» 5th ANNUAL TAUB RETREAT, October 2014

» In the Lab: Asa Abeliovich

» In the Lab: Lorraine N. Clark

» In the Lab: Ulrich Hengst

» Cognitive Neuroscience of Aging Laboratory

» In the Lab: Ottavio Arancio

» Clinical Research: Karen Marder

» Scott Small Laboratory

» Michael Shelanski Laboratory

» Laboratory for Genetic Epidemiology

» Karen Duff Laboratory




DYSREGULATION OF MICRORNA-219 MODULATES TAU PROTEOSTASIS AND CONTRIBUTES TO MEMORY AND CIRCADIAN RHYTHMS DYSFUNCTION

Ismael Santa-Maria Perez, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Intracellular accumulation of hyperphosphorylated misfolded tau proteins is one of the main hallmarks in many neurodegenerative diseases. Hence, knowledge and understanding of disease mechanisms that impact tau production and accumulation, altering overall tau proteostasis and behavior is critical. Recently, abnormalities in microRNAs (miRNAs) have been linked to neurodegeneration. However, the extent to which dysregulation of microRNAs directly alters tau proteostasis by modifying tau expression, phosphorylation, or both is unclear. Each microRNA is capable of binding to and silencing many target transcripts, providing an additional level of regulation that complements canonical transcriptional pathways. We hypothesize that dysregulation of microRNAs alter post-transcriptional regulation of tau and tau candidate kinases, exacerbating abnormal accumulation of toxic tau species and neurodegeneration. We have previously shown that microRNA-219-5p (miR-219) is downregulated in Alzheimer’s disease (AD) and related tauopathies and that miR-219 directly binds to the tau mRNA 3' untranslated region and silences its expression in mammalian cells and in Drosophila. We have recently observed a significant change on phosphorylated tau at AD-related epitopes in response to suppression or overexpression of miR-219 in neuronal cells. Bioinformatics analysis predicts miR-219 to target Glycogen synthase kinase 3 beta, Calcium/calmodulin-dependent protein kinase 2 gamma subunit and Tau tubulin kinase 1, and we have found that miR-219 directly binds the 3' UTR and represses synthesis of these kinases.

Next, we explored the role loss of miR-219 function plays in AD-associated phenotypes using Drosophila. miR-219 knockout flies develop short term memory deficits and, regarding circadian rhythms, we have observed phenotypes which might involve defective core clock operation, altered clock output, or perhaps aberrant environmental perception. Together, our findings support loss of miR-219 modulate tau proteostasis and contributes to memory and circadian rhythm alterations associated with impaired cognition and AD.


GENETICS OF MEMORY IN THE AGING BRAIN

Sandra Barral Rodriguez, PhD
Assistant Professor of Neurogenetics (in Neurology, the Gertrude H. Sergievsky Center, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain) at Columbia University Medical Center

Why do some people experience memory decline during normal aging, while others remain cognitively intact at an advanced age, and others develop severe cognitive impairment? Elderly cohort studies have shown that memory changes with aging are very heterogeneous. However, the nature and extent of these changes have been predominantly studied in the context of neurodegenerative disorders, such as Alzheimer's disease. Establishing the patterns of memory function among cognitively healthy elderly is crucial to gaining a complete understanding of brain aging. By applying statistical methodology to genomics data, we can investigate the genetics of memory in the aging brain. Analyses of different types of genomic data (genotyping arrays, whole genome/whole exome sequencing data), using diverse statistical genetic approaches (GWAS, linkage analysis, etc.), can lead to the discovery of genetic variants associated with cognitive function in healthy populations, which may allow us to identify healthy individuals who are at highest risk for the development of dementia.


THE USE OF HUMAN BRAIN TISSUE FOR TRANSLATIONAL RESEARCH AT TAUB

Andrew F. Teich, MD, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Human brain tissue is a vital resource for translational neurodegenerative disease research. We first outline the standard procedures for obtaining autopsy brain tissue from the New York Brain Bank at Columbia University. We then describe work from the Teich laboratory demonstrating how analysis of transcriptomic data from human brain tissue can be used in AD research. Normal Pressure Hydrocephalus (NPH) is a clinical syndrome characterized by cognitive impairment, urinary incontinence, and ataxia. Symptomatic relief is often achieved by placement of a cortical CSF shunt. NPH patients with amyloid plaques on biopsy and/or an elevated CSF phospho-tau/beta-amyloid ratio are less responsive to shunting, and are thought to be "pre-AD." We examine whether amyloid plaques on biopsy and three separate CSF measurements (beta-amyloid, total tau, and phospho-tau) correlate with changes in gene expression in shunt biopsies from NPH patients. We find that phospho-tau is the primary variable that correlates best with changes in gene expression in NPH biopsies, and that phospho-tau appears to correlate with up-regulation of inflammatory ontology groups and downregulation of gene translation ontology groups. Based on these findings, we hypothesize that phospho-tau may be directly or indirectly involved in some of the earliest transcriptomic changes in AD brain.


MOLECULAR IMAGING IN NEUROLOGY: A CRITICAL PARTNERSHIP

Akiva Mintz, MD, PhD
Professor of Radiology at the Columbia University Medical Center


NEUROPSYCHIATRIC SYMPTOMS AND ANTIPSYCHOTIC USE IN ALZHEIMER'S DISEASE

Devangere P. Devanand, MBBS, MD
Professor of Psychiatry (in Neurology and in the Gertrude H. Sergievsky Center) at the Columbia University Medical Center

Symptoms of psychopathology occur frequently in patients with Alzheimer's disease and pose major difficulties in patient management. Psychosis, agitation, and aggression are the syndromes that the clinician is commonly called to treat. Studies of antipsychotic treatment for symptoms of psychosis and behavioral decontrol indicate a narrow therapeutic window, with efficacy at low doses but side effects developing at even moderate doses. Overuse of antipsychotics in nursing homes has led to regulations to decrease prescribing, but a multicenter discontinuation trial showed an increased risk of relapse after discontinuation of the antipsychotic risperidone that was evident even 8 months after discontinuation. Striking the balance between the need for antipsychotic treatment and the risk of toxicity, including increased mortality, is the clinician’s task. While anticonvulsants are commonly used to treat agitation and aggression, results from controlled trials are not supportive. Citalopram, an SSRI antidepressant, showed modest efficacy in a multicenter trial but QTc prolongation occurred at the dose of 30 mg daily used in that study. Newer medications are under investigation, including antipsychotics like brexpiprazole and low-dose lithium as well as dextromethorphan-quinidine, to treat agitation in Alzheimer's disease.


FUNCTIONAL CONNECTIVITY AND NEGATIVE BOLD RESPONSE IN DEFAULT MODE NETWORK

Qolamreza (Ray) Razlighi, PhD
Assistant Professor of Neuroimaging (in Neurology and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

The topography of the default mode network (DMN) can be obtained with one of two different functional magnetic resonance imaging (fMRI) methods: either from the spontaneous but organized synchrony of the low-frequency fluctuations in resting-state fMRI (rs-fMRI), known as "functional connectivity", or from the consistent and robust deactivations in task-based fMRI (tb-fMRI), here referred to as the "negative BOLD response" (NBR). These two methods are fundamentally different, but their results are often used interchangeably to reflect the brain's resting-state, baseline, or intrinsic activities. In this study, we highlight the difference between the two DMNs obtained by the two aforementioned methods and demonstrate that the NBR in DMN regions can be significantly altered without causing any change to the underlying functional connectivity. Furthermore, we present preliminary evidence that in the DMN, the NBR is more relevant to task performance than is functional connectivity. This study concludes that the NBR and functional connectivity of the DMN are representative of two different but overlapping neurophysiological processes, and should thus be differentiated in studies investigating the brain-behavior relationship in both healthy and diseased populations.


ATOMIC STRUCTURES OF TAU FILAMENTS FROM ALZHEIMER'S DISEASE BRAIN: IMLICATIONS FOR FIBRIL PROPAGATION ARISING FROM PATIENT-BASED STRUCTURAL BIOLOGY

Anthony Fitzpatrick, PhD
Assistant Professor of Biochemistry & Molecular Biophysics, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. Alzheimer's disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here, we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau, which adopt a combined cross-β / β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.


BREAKING DOWN SUBJECTIVE COGNITIVE DECLINE

Stephanie Cosentino, PhD
Associate Professor of Neuropsychology (in Neurology, the Gertrude H. Sergievsky Center and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain), Columbia University Medical Center

In the field of cognitive aging, there is an urgent push to identify the markers of pre-clinical Alzheimer's disease (AD) in order to move pharmacologic intervention earlier in the disease spectrum, to a time when it can be most effective. There is growing interest in subjective cognitive decline (SCD) as a potential marker of pre-clinical AD. SCD, or the perception that one's cognition has declined despite "normal" performance on standard diagnostic testing, is an important health outcome that is concerning to many older adults, and leads some to seek medical attention. Determining the extent to which SCD may serve as a pre-clinical marker of AD is of great value, as SCD is non-invasive, inexpensive, and easily obtainable. However, SCD is a complex, multi-factorial construct. In order to determine its true utility as a marker of pre-clinical AD, it is critical to comprehensively characterize the factors that influence SCD, and that affect the degree to which it reflects "true" or actual cognitive functioning. Indeed, SCD is certain to reflect not only a person's actual cognitive functioning but a variety of factors, including those that are task-specific (i.e., how SCD is measured). We examined several types of SCD, including age-anchored SCD (e.g., how is your memory compared to others your age?) and retrospective SCD (e.g., how is your memory compared to 5 years ago?), in relation to novel cognitive outcomes sensitive to AD biomarkers. Depending on how it was measured, SCD mapped on differently to cognitive outcomes, suggesting that a subtle difference in the way we query individuals about their cognition can change the type of underlying cognitive abilities that the SCD judgments reflect. Results from this line of research will inform guidelines for how to measure and interpret SCD in older adults, and will set the stage for determining how and when SCD may be used as an indicator of preclinical Alzheimer's disease.


SPINE STRUCTURAL DYNAMICS IN HEALTH AND DISEASE

Inbal Israely, PhD
Assistant Professor of Pathology and Cell Biology (in Neuroscience and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Brain circuits can be structurally rearranged with experience, and synaptic connections grow and are eliminated during development and in adult brains. Dendritic spines, on which most excitatory synapses are located, are highly dynamic and are structurally modified by activity. These changes may underlie the long term remodeling of neural circuits and the encoding of information.

Protein synthesis is a critical regulator of structural plasticity of spines, and in particular, we have established its importance during competition and cooperation between neighboring inputs that undergo potentiation. The structural correlates of long lasting synaptic depression are less clear. Here, we study a metabotropic glutamate receptor (mGluR) dependent form of long lasting synaptic depression that requires the induction of new protein synthesis. Of relevance, impairments in mGluR plasticity have been implicated in several neurodevelopmental disorders, including Fragile X syndrome, and more recently in Alzheimer’s disease, resulting in both cognitive and spine structural abnormalities.

We take advantage of 2-photon mediated activation of caged glutamate to stimulate single spines with high spatial and temporal specificity. We developed a paradigm by which to induce robust mGluR mediated synaptic depression, and show that this leads to long lasting shrinkage of individual spines, which is sensitive to protein synthesis blockade. Since the mouse model of Fragile X has abnormally high protein translation, we tested whether neurons from this background have impaired synaptic competition. Indeed, we find normal mGluR depression at single spines from Fragile X neurons; however, these mutant neurons do not undergo synaptic competition, resulting in excess depression at all stimulated inputs. Further studies will determine whether impaired competition could be a more general mechanism underlying neural dysfunction. Thus, we combine the precise stimulation of defined inputs with whole cell electrophysiological recordings and imaging, in order to understand how activity influences synaptic structure and function, in health and disease.


THE CAMKK2-AMPK PATHWAY MEDIATES THE SYNAPTOTOXIC EFFECTS OF AΒ42 OLIGOMERS THROUGH MFF-DEPENDENT MITOCHONDRIAL FISSION AND ULK2-DEPENDENT MITOPHAGY

Franck Polleux, PhD
Professor of Neuroscience, Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University


KEYNOTE PRESENTATION: PROGRESS AND CONTROVERSIES IN PROTEIN MISFOLDING IN ALZHEIMER'S AND PARKINSON'S DISEASES

Dennis J. Selkoe, MD
Vincent and Stella Coates Professor of Neurologic Diseases, Harvard University, Co-director, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital


NEURITIC LOCALIZATION OF MICROSATELLITE REPEAT RNAS AND TRANSPORT GRANULE DYSFUNCTION IN NEURODEGENERATION

Alondra Schweizer Burguete, PhD
Associate Research Scientist (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Following Dr. Selkoe's keynote presentation Dr. Alondra Schweizer Burguete talked about a subset of neurodegenerative disorders, including Huntington's and ALS/FTD, that are caused by expansion of short nucleotide sequences termed microsatellite repeats. She discussed how the resulting repeat RNAs can associate with transport granules that get to distal neuritic segments. Because the RNAs generated from microsatellite expansion disease loci have high secondary structure content, reminiscent of mRNA localization signals, she hypothesized that such disease-associated repeat RNAs might interact with the mRNA localization and translation machinery with deleterious consequences. So far her results have shown that neuritic localization of expanded repeat RNA correlates with fewer primary branches in rat primary spinal cord culture, that CAG and GGGGCC expansion also results in dendritic defects in a Drosophila model, and furthermore that transport granule components identified as modifiers in the fly are misregulated in patient-derived iPSNs.


PHOSPHORYLATION-MEDIATED CLEARANCE OF AMYLOID-LIKE ASSEMBLIES IN MEIOSIS

Luke E. Berchowitz, PhD
Assistant Professor of Genetics and Development (in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain)

Amyloids are fibrous protein assemblies that are often described as irreversible and intrinsically pathogenic. However, yeast cells employ amyloid-like assemblies of the RNA-binding protein Rim4 to control translation during meiosis. Formation and clearance of these assemblies is developmentally regulated. We sought to determine how yeast cells clear amyloid-like Rim4 in coordination with developmental cues intrinsic to meiotic progression. We show that RIM4 mutants that cannot be phosphorylated within their intrinsically disordered region exhibit aberrant persistence of amyloid-like assemblies. There appear to be no critical residues that must be modified. Rather, our data support a model in which a threshold amount of Rim4 phosphorylation is required for clearance. Failure to clear Rim4 assemblies delays meiotic progression, and a single copy of an un-clearable RIM4 exerts a dominant negative phenotype. Furthermore, we show that Ime2 is the kinase that phosphorylates Rim4 and triggers its disassembly, and that this disassembly precedes processing by the proteasome. Together, these results indicate that yeast cells rapidly disassemble and clear amyloid-like structures through hyperphosphorylation and proteasomal processing during meiosis.


ENDOSOMAL SORTING AND DEGRADATION OF TAU IS INHIBITED BY GLUCOCORTICOIDS

Joāo Vaz-Silva, Student, Graduate School of Arts and Sciences, Columbia University Medical Center
Laboratory of Dr. Clarissa Waites



MONITORING MICROTUBULE DYNAMICS AT SYNAPTIC CONTACTS IN HIPPOCAMPAL NEURONS CHALLENGED WITH OLIGOMERIC AΒ1-42

Xiaoyi Qu, Student, Graduate School of Arts and Sciences, Columbia University Medical Center
Laboratory of Dr. Francesca Bartolini

Growing evidence indicates that control of microtubule dynamics in axons, dendrites and at synaptic contacts is critical for neuronal function. However, virtually nothing is known about whether anomalies in microtubule dynamics is a primary activity of oligomeric Aβ1-42 (Aβ) that initiates synaptotoxicity. We found that the formin mDia1-mediated stabilization of dynamic microtubules in dendrites and axons drives tau-dependent Aβ synaptotoxicity. To test whether these changes further occur at synapses and are directly responsible for synapse loss, we have recently developed microscopy assays that measure microtubule invasions into dendritic spines and microtubule contacts with presynaptic boutons of cultured hippocampal neurons. We observed that Aβ perturbs both pre- and postsynaptic microtubule behavior prior to loss of synapses, and that changes to synaptic microtubules are dependent on formin function. We are currently examining the role of mDia1 and tau in synaptic microtubule behavior, and how these changes are modulated by neuronal activity.



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