Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
June 2017

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» #1 Memory-Enhancing Effects of GEBR-32a, a New PDE4D Inhibitor Holding Promise for the Treatment of Alzheimer's Disease

» #2 #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

Post translational Remodeling of Ryanodine Receptor Induces Calcium Leak Leading to Alzheimer's Disease like Pathologies and Cognitive Deficits

   Michael Shelanski, MD, PhD   
Andrew R. Marks, MD     Michael Shelanski, MD, PhD
Andrew F Teich, MD, PhD      
Andrew Teich, MD, PhD    Ottavio Arancio, MD, PhD   

The "calcium hypothesis" of Alzheimer's disease (AD) has been around for many years, and focuses on the pathological role of elevated intracellular calcium that is reproducibly demonstrated in a variety of AD animal models. Intracellular calcium is a signal that mediates a wide-range of processes, including learning and memory, and several groups have proposed that abnormally elevated calcium levels in AD may contribute to the observed impairment in learning and memory. Elevated intracellular calcium in AD has been proposed to come from both outside the cell as well as from the endoplasmic reticulum (ER). This latter source of calcium enters the cytoplasm in part through ryanodine (RyR) receptors. Although RyR dysfunction has been previously reported in AD animal models, the molecular mechanism of RyR dysfunction has remained largely unexplained until now.

Published this month in Acta Neuropathologica, the laboratory of Dr. Andrew Marks, in collaboration with Drs. Michael Shelanski, Andrew Teich and Ottavio Arancio from the Taub Institute, has taken a major step towards a better understanding of RyR dysfunction in AD. In this study, Marks and colleagues show that RyR2 channels (the major RyR isoform in brain) undergo post-translational remodeling characterized by PKA phosphorylation, oxidation/nitrosylation, and depletion of the channel stabilizing subunit calstabin2 (FKBP12.6) in human sporadic AD, as well as in two well established mouse models of AD (APP+/−/PS1+/− and 3 × Tg-AD). The authors then demonstrate that these post-translational modifications to the RyR2 channels are linked to increased calcium leak from the ER, which mechanistically links these findings to the elevated intracellular calcium levels that are postulated to cause learning and memory impairment in AD.

Are these findings therapeutically relevant? Marks and colleagues perform two separate rescue experiments that suggest they are. First, Marks and colleagues fixed the leaky RyR2 channels in APP+/−/PS1+/− and 3 × Tg-AD mice by orally administering Rycal S107, which is a compound that prevents stress-induced dissociation of calstabin2 from the RyR2 complex. This stabilization of the RyR2 complex inhibited calpain activity and AMPK-dependent tau phosphorylation, and improved hippocampal plasticity and cognitive function. Remarkably, this intervention also reduced amyloid plaque pathology. As a follow-up to this study, Marks and colleagues then crossed APP+/−/PS1+/− mice with RyR2-S2808A+/+ knock-in mice, which have RyR2 channels that are resistant to PKA phosphorylation. This crossing resulted in mice with improved cognition as well as reduced amyloid plaques. Finally, Marks and colleagues investigated the physiologic consequences of a constitutively active RyR2 channel. Mice harboring constitutively leaky PKA phosphomimetic RyR2-S2808D+/+ channels exhibited cognitive and synaptic abnormalities at an early age, consistent with the observation that abnormal RyR2 function may contribute to synaptic and cognitive impairment in AD.

In summary, this study demonstrates a mechanistic link between post-translational modification of RyR2 channels and cognitive dysfunction in AD. Importantly, the therapeutic implications of this finding are nicely demonstrated, and will hopefully spurn new therapies aimed at alleviating ER calcium leak and associated learning and memory abnormalities in AD patients.

Andrew R. Marks, MD
Chairman, Department of Physiology
Founding Director, Wu Center for Molecular Cardiology
Professor, Physiology and Cellular Biophysics; Medicine

Michael Shelanski, MD, PhD
Professor of Pathology & Cell Biology
Henry Taub Professor of Alzheimer's Disease Research
Co-Director, Taub Institute for Research on Alzheimer's Disease and the Aging Brain

Ottavio Arancio, MD, PhD
Professor of Pathology and Cell Biology (in the Taub Institute)

Andrew Teich, MD, PhD
Assistant Professor of Pathology & Cell Biology

Neuropathologic Features of TOMM40 '523 Variant on Late-Life Cognitive Decline

Philip De Jager, MD, PhD, MMSc

In the past 5 years, there has been a tremendous growth in our understanding of the role of genetic variation in the onset of Alzheimer’s disease (AD) and age-related cognitive decline. However, much of this genetic architecture remains to be found and even well-known regions of the human genome can harbor some surprises. Apolipoprotein E (APOE) is the best-known susceptibility gene for late-onset Alzheimer disease (AD). The APOE locus has long been suspected to harbor a non-APOE variant that confers susceptibility to aging-related pathologies and cognitive decline. Recent work has focused on the TOMM40 '523 variant of different lengths that is found near the APOE gene, and the present manuscript, now published online ahead of print in Alzheimer's & Dementia, elaborates its role. Here, new Taub faculty member Dr. Phil De Jager, first author Dr. Lei Yu from Rush Alzheimer's Disease Center, and colleagues examine the role of common neuropathologies in the relationship between TOMM40 '523 genotype and longitudinal cognitive decline, leveraging cognitive, genetic, and neuropathologic data from a large number of community-based older Caucasian Americans who were followed annually for up to 21 years and had undergone brain autopsy after death.

To avoid the effect of the disease-related APOE ε2 and ε4 variants, Dr. De Jager and colleagues focused their analysis on the ε3/3 homozygotes: using ε3/3 homozygotes with at least one copy of the '523 very long (VL) genotype as a reference, both '523 long (L) carriers and '523-short/ short (S/S) genotype had faster cognitive decline. The association of '523-L with cognitive decline was attenuated and no longer significant after controlling for AD-related pathologies, suggesting that enhanced pathology may be the mechanism for this variant. By contrast, the association of '523-S/S was unchanged, which suggests that its mechanism may be distinct. Thus, Yu et al. elaborate the role and mechanism of the TOMM40 susceptibility allele, independent of the role of the well-known APOE- ε2 and ε4 haplotypes, demonstrating that there are two distinct TOMM40 '523 signals in relation to late-life cognitive decline: one signal primarily acts through AD and other common neuropathologies, whereas the other operates through a different mechanism.

Overall, this manuscript is one more step on the path to understanding how variation in the human genome contributes to making human subjects susceptible to developing AD with advancing age. In most individuals with AD, it is the combination of many variants like TOMM40 '523 with environmental risk factors that lead to the accumulation of brain pathology, loss of cognitive function, and, ultimately, a diagnosis of dementia.

Figure 2: The effects of TOMM40 '523 genotypes on annual rate of cognitive decline before and after the adjustment for neuropathologies. See full caption in manuscript.

Philip De Jager, MD, PhD, MMSc
Professor of Neurology (in the Taub Institute, the Precision Medicine Initiative, and the Center for Translational and Computational Neuro-immunology)
Director, Division of Cognitive Neuroscience


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