Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
August 2016

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» 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

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

Karen Duff, PhD    Hongjun (Harry) Fu, PhD

In a study recently published in the journal PLoS One, a team led by Taub faculty member Dr. Karen Duff has provided evidence that the spread of tau pathology out of entorhinal cortex (EC) into neocortex is associated with neurotoxicity and cognitive impairment in aged EC-tau transgenic mice, which mimics what happens in patients with Alzheimer's disease (AD). It validates the idea that neurotoxicity is associated with the spread of tauopathy. The team's lead scientist, Dr. Hongjun (Harry) Fu, used a variety of sophisticated techniques to study the temporal relationship between tau pathology spread, degeneration, and cognition, which can help define timepoints when therapeutic interventions may be effective.

Fu et al. demonstrated the power of the immunolabeling-enabled three-dimensional imaging of solvent cleared organs (iDISCO) to observe tau pathology in deep structures of the EC-Tau mouse brain, which has greatly facilitated the tracking of tau pathology progression through the mouse brain’s anatomical networks. Using iDISCO, they found several areas affected by tau pathology in older EC-Tau mice that had not been previously identified by 2D immunostaining: the amygdala (AM), piriform cortex (Pir), and anterior olfactory area (AO). Importantly, their findings demonstrate the temporal and spatial relationship between areas as they become affected by tau pathology, including, for the first time in this mouse model, the neocortical areas. As in human AD, the first signs of cognitive impairment correlate with overt tau pathology and cell loss as well as gliosis in the EC, which in turn correlates with the first appearance of tau pathology in the neocortex. Interestingly, they also found that pathological tau was mainly colocalized with neuronal markers, but not microglia or astrocyte markers, although the gliosis is associated with the spread of tau pathology.

Representative snapshots of 3D images of tau staining in EC-Tau mice using iDISCO. Different brain regions with tau pathology are indicated by superimposed artificial colors. The regions with no or sparse tau immunoreactivity are not colored.

These findings, which were also reported by ALZFORUM on August 3rd, help improve understanding of the relationship between the spread of tau pathology, gliosis, and neurodegeneration. Tau pathology and atrophy has been shown in the AM of human AD patients and the Pir, AO and AM have been proposed to play very important roles in olfaction, emotion, and memory in humans. Tau pathology in those areas could also explain the olfactory deficits and psychiatric symptoms seen in patients with early AD. Thus, this EC-Tau mouse model may be a potential model for studying not only cognitive deficits but also olfactory and psychiatric problems seen in patients with early AD.

Karen Duff, PhD
Professor of Pathology and Cell Biology (in Psychiatry and in the Taub Institute)

Hongjun (Harry) Fu, PhD
Associate Research Scientist in the Taub Institute

LRRK2 and RAB7L1 Coordinately Regulate Axonal Morphology and Lysosome Integrity in Diverse Cellular Contexts

Asa Abeliovich, MD, PhD   Tomoki Kuwahara, PhD

Over the past decade, human genetics researchers, including Drs. Lorraine Clark, Karen Marder, and others in the Taub Institute, have made great strides in identifying genes associated with familial or non-familial forms of Parkinson's disease (PD). However, it has been challenging to understand how these genes, or mutations in these genes, play a role in neurodegeneration.

The Abeliovich laboratory has used a variety of model systems to explore the function of several PD-associated genes, including LRRK2. A surprising finding, overall, is that the functions of many of these genes can be linked directly to endosomal intracellular trafficking mechanisms that bring a variety of cargo to the lysosome for degradation. In a recent manuscript, published this month in Scientific Reports, Dr. Abeliovich's team, including first author Dr. Tomoki Kuwahara, generated mice and nematodes deficient in LRRK2 and, in both contexts, found evidence of defective intracellular trafficking to lysosomes, leading to lysosomal abnormalities.

In mice, a surprising aspect is that loss of LRRK2 leads to lysosomal defects, but these are found in kidney proximal tubule cells of older animals, and not in the central nervous system. In pursuit of how LRRK2 may be involved, Kuwahara et al. studied a second PD-associated gene, RAB7L1, and show evidence that the two genes function coordinately in the regulation of intracellular trafficking, both in mice and in nematodes. Furthermore, mice deficient in RAB7L1 look very similar to mice deficient in LRRK2, and the mutations are non-additive. Future work will pursue the relationship between the normal functions of these genes and neurodegeneration in the brain. A key player in this project, which required analysis of kidney pathology, was Dr. Vivette D'Agati in the Department of Pathology and Cell Biology.

Asa Abeliovich, MD, PhD
Associate Professor of Pathology and Cell Biology, and Neurology (in the Taub Institute)

Tomoki Kuwahara, PhD

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