Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
November 2015

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» #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 A╬▓ 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 ┼ĺ┬▒ 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

The Reference Ability Neural Network Study: Life-time stability of reference-ability neural networks derived from task maps of young adults

Christian Habeck, PhD<    Yaakov Stern, PhD
Christian Habeck, PhD Yaakov Stern, PhD

As recently published in NeuroImage, a new study by Drs. Christian Habeck, Yaakov Stern, and colleagues analyzed the data of 191 normal adults in the age range 20 to 77 who were imaged in a functional Magnetic Resonance Imaging (fMRI) scanner while performing 12 cognitive tasks. The tasks were chosen to represent the 4 cognitive "Reference Abilities" (estimated with 3 different tasks per ability): (1) memory, (2) fluid reasoning, (3) perceptual speed, and (4) vocabulary. The first three of the abilities have generally been observed to decline with aging, while the fourth usually stays unchanged or even improves with aging. For the fMRI data, after some pre-processing and linear time-series modeling, the investigators had one activation map per participant for each of the 12 tasks available. They applied a relatively simple mathematical technique to the activation maps called "linear indicator regression" to derive four activation patterns underlying the four Reference Abilities. The derivation was only performed in the activation maps of the participants aged 30 and younger. Habeck et al. reasoned that the restriction to young adults would allow them to achieve the best possible manifestation of the underlying Reference Ability Neural Networks (RANNs), without any influence of aging.

The activation patterns, although derived in the young participants, can be applied prospectively to the activation maps of the middle-aged and older participants (aged 31 and above.) A simple test of the validity of these patterns is whether they can accurately classify the activation maps into the correct Reference Ability. This means that for each activation map, one of four labels (1=memory, 2=fluid reasoning, 3=perceptual speed, and 4=vocabulary) can be predicted, depending on the observed topographic similarities of the activation map in question, with each of the four activation patterns derived in the young participants. Somewhat surprisingly, Habeck et al. found a high classification accuracy of 81% in the middle-aged and older participants, much better than the chance level of 25% (1 out of 4 abilities). Classification accuracy could also be computed on an individual-participant level and was found not to be associated with individual participant's age in the people aged 31 and older. However, classification accuracy was associated with verbal intelligence and total brain volume, such that participants with higher verbal intelligence and higher brain volume also showed higher classification accuracy, which implies better specificity of the derived networks to their associated cognitive processes. For each of the four activation patterns and each participant, the overall level pattern utilization can also be computed which likewise did not show any association with individual participant's age.

Figure above: 4 activation patterns capturing the Reference Abilities: (1) memory (=MEM), (2) fluid reasoning (=FLUID), (3) perceptual speed (=SPEED), and (4) vocabulary (VOCAB). The lowest row shows an activation pattern common to all tasks. Red color indicates increased activation relative to a rest condition where participants viewed a blank screen; blue color indicates decreased activation.

These findings imply that the networks underlying basic cognitive processes (at least as derived in the current study framework), and their manner of operating, are stable across the adult lifespan. The authors suggest that, with additional data, these networks can be derived for each age decade, which allows the observation of topographic changes with age and the influence of structural brain variables, like cortical volume, cortical thickness and amyloid deposition. From a translational standpoint, the networks might also hold diagnostic and prognostic power above and beyond brain-structural health for predicting cognitive dysfunction.

Christian Habeck, PhD
Associate Professor of Neuroimaging (in Neurology and in the Taub Institute)

Yaakov Stern, PhD
Professor of Neuropsychology (in Neurology, Psychiatry, the Sergievsky Center, and the Taub Institute)

Novel Selective Calpain 1 Inhibitors as Potential Therapeutics in Alzheimer's Disease

Ottavio Arancio, MD, PhD

The vast majority of failing clinical efforts against Alzheimer's disease is directed to the problem of amyloidogenic protein deposition, because proteinaceous aggregates consisting of deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles are the major histopathological hallmarks of the disease. Recently published in the Journal of Alzheimer's Disease, a new study by the laboratory of Dr. Ottavio Arancio, including colleagues from the Taub Institute and other academic institutions, focuses, in turn, on preserving synaptic functionality. Such an approach is justified by ample evidence suggesting that Alzheimer's disease starts as a synaptic disorder, and is potentially effective in all diseases involving hyper-activation of the calpain system. Previous work by the Arancio Laboratory found that inhibition of calcium-dependent enzymes called calpains improved memory and synaptic transmission in a mouse model of Alzheimer's disease (AD). This led to an effort to translate findings on the etiopathogensis of AD, and on possible useful strategies to counteract the disease, into therapeutics.

NYC438 and NYC488 chemical structures.

In the current study, Fà et al. were able to validate the high therapeutic potential of two novel chemical entities inhibiting calpains, known as NYC438 and NYC488. They used a strategy including a phenotypical screening of calpain inhibitors developed via medicinal chemistry refined through a target-based computational approach. The inhibitors were screened using a synaptic assay that demonstrated that the novel compounds are capable of restoring normal communication among cells in the brain. Most importantly, the novel molecules were effective in restoring learning and memory in a mouse model of Alzheimer's disease, while they were devoid of toxic effects even when administered chronically at doses largely higher than the minimal effective dose (at least > 10-fold, according to the FDA recommendations). The availability of a new series of effective, non-toxic therapeutics, exerting their activity on the molecular mechanisms of the disease, is a positive step toward a better cure for Alzheimer's disease and any other disease associated with calpain overactivation.

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


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