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TaubCONNECT Research Perspectives:
June 2018





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May 2018:

» #1 Whole Genome Sequencing in Caribbean Hispanic Families Associated with Late-Onset Alzheimer's Disease (LOAD)

» #2 Oligomeric Aβ1-42 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 White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes

» #2 Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia


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

» #2 An Inflammation-Related Nutrient Pattern is Associated with Both Brain and Cognitive Measures in a Multiethnic Elderly Population


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


December 2017:

» #1 Neuronal Hyperactivity Due to Loss of Inhibitory Tone in APOE4 Mice Lacking Alzheimer's Disease-Like Pathology
and
» The Endosomal–Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo

» #2 The Historical Progression from ADL Scrutiny to IADL to Advanced ADL: Assessing Functional Status in the Earliest Stages of Dementia

November 2017:

» First Place: A CSF Proteomic Screen Links Retromer to Alzheimer's Pathogenic Pathways and Suggests Endosomal-Trafficking Biomarkers

» First Place: Microglia Identity in the Aged and AD Human Brain

October 2017:

» #1 Intra-Axonal Synthesis of SNAP25 is Required for the Formation of Presynaptic Terminals

» #2 Increased Localization of APP-C99 in Mitochondria-associated ER Membranes Causes Mitochondrial Dysfunction in Alzheimer Disease

September 2017:

» #1 Atabilization of Dynamic Microtubules by mDia1 Drives Tau-dependent Aβ1-42 Synaptotoxicity

» #2 An xQTL Map Integrates the Genetic Architecture of the Human Brain's Transcriptome and Epigenome

August 2017:

» #1 Abolishing Tau Cleavage by Caspases at Aspartate421 Causes Memory/Synaptic Plasticity Deficits and Pre-Pathological Tau Alterations

» #2 Mediterranean Diet and Cognitive Health: Initial Results from the Hellenic Longitudinal Investigation of Ageing and Diet (HELIAD)

July 2017:

» #1 Abnormal Neurofilament Inclusions and Segregations in Dorsal Root Ganglia of A Charcot-Marie-Tooth Type 2E Mouse Model

» #2 LTP and Memory Impairment Caused by Extracellular Aβ and Tau Oligomers is APP-Dependent

June 2017:

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

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

May 2017:

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

» #2 An Approach to Studying the Neural Correlates of Reserve

April 2017:

» #1 Brain Atrophy Can Introduce Age-Related Differences in BOLD Response

» #2 Age-Related Biomarkers in LLFS Families With Exceptional Cognitive Abilities

March 2017:

» #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

February 2017:

» #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

January 2017:

» #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




Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer's Disease

Catherine Marquer, PhD
Catherine Marquer, PhD

The three forms of AD—familial AD (FAD), Down syndrome-related AD (DS/AD), and sporadic AD (SAD)—share common clinical and neuropathology signatures, but their genetic causes differ. Early-onset FAD is caused by mutations in the APP, PSEN1, or PSEN2 gene and DS/AD is due to triplication of human chromosome 21 (Hsa21), while the most potent genetic risk factor for SAD is the ε4 allele of the APOE gene (APOE4). In the present study, published in Cell Reports, the laboratory of Dr. Catherine Marquer, along with collaborators from Taub and other institutions, asked whether elevated levels of synaptojanin 1 (SYNJ1), a key regulator of synaptic function, could be a common denominator to all three forms of AD.

Indeed, SYNJ1 levels are elevated in individuals at high risk for developing DS/AD (Martin et al., 2014) and SAD (Zhu et al., 2015), but what about FAD? Previous work performed in cellular and murine models in the Taub Institute by Drs. Gil Di Paolo and Tae Wan Kim supported that SYNJ1 may play a role in the physiology of FAD (Landman et al., 2006; McIntire et al., 2012), but its involvement in human FAD remained unknown. In the present study, Miranda, Herman, Cheng et al., in collaboration with Dr. Joseph H. Lee, asked whether SYNJ1 was associated with human FAD. They showed that variants in SYNJ1 are associated with age of onset and long-term memory deficits in an early-onset FAD cohort of Caribbean Hispanic families with the PSEN1-G206A founder mutation. Further, they demonstrated that variants in SYNJ1 are also associated with age of onset in the EFIGA cohort of late-onset FAD. These results in human FAD cohorts thus strongly suggest that SYNJ1 may play a role in all three forms of AD.


Figure: Findings from the Marquer lab, combining human genetics, human autopsy brain samples, and behavior and in vivo electrophysiology studies in a transgenic mouse model, strongly support that SYNJ1 plays a role in memory deficits in all three forms of AD

Dr. Marquer and co-investigators then explored whether the elevated levels of SYNJ1 observed in DS/AD and SAD directly affected cognition. For DS/AD, they teamed up with Drs. Elizabeth Head, Frederick A. Schmitt and Ira T. Lott (University of Kentucky and University of California, Irvine). They found that increased SYNJ1 levels in autopsy brains from adults with DS/AD are inversely correlated with synaptophysin levels, which are commonly used as an estimation of the number of synapses. No such correlation was observed in younger individuals with DS, whose SYNJ1 levels are similar to those of disomic controls.

For SAD, they recapitulated the SYNJ1 overexpression levels described in SAD in a transgenic mouse model, Tg(Synj1) (Voronov et al., 2008). Their behavior experiments revealed that, while 9-month old transgenic animals performed similarly to the controls, 19-month old transgenic animals showed hippocampal cognitive deficits. Marquer and colleagues found that increased levels of Synj1 did not impair learning per se in older animals, but caused a specific defect in long-term memory retention. Using in vivo recordings, in collaboration with Dr. Abid Hussaini, they showed that this defect is due to hippocampal hyperexcitability and, more specifically, to a dramatic alteration in the spatial reproducibility of hippocampal place fields, which may affect memory consolidation.

Taken together, their data strongly argue that SYNJ1 plays a role in the function of place cells in the aging hippocampus, with critical implications for memory deficits in all three forms of AD and their possible treatment.

Catherine Marquer, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute)
cm3244@cumc.columbia.edu



Preparation of Tau Oligomers After the Protein Extraction from Bacteria and Brain Cortices


Ottavio Arancio, MD, PhD

Tau protein is the main component of neurofibrillary tangles that constitute one of the histological markers of Alzheimer’s disease (AD). Initially, it was thought that neurofibrillary tangles are the major toxic entities in AD, although recent findings seem to challenge this idea, suggesting that synaptic dysfunction and neuronal dearth are mainly related to early-stage tau oligomers. There is a growing body of evidence suggesting that tau oligomers induce the early neuronal damage and, subsequently, the learning and memory impairment characterizing AD. Injection of the full-length recombinant oligomerized tau in the mouse brain activates the mitochondrial apoptotic pathway and reduces the levels of proteins participating in synaptic transmission. Accordingly, tau oligomers, not fibrils or monomers, impair memory consolidation in mice injected with tau oligomers purified from human Alzheimer’s brains or recombinant human tau. In particular, tau oligomers disrupt storage of new memories rendering mice incapable of remembering new information. Interestingly, tau oligomers are responsible for the neuronal damage occurring in AD, even before the aggregation of Αβ fibrils.

Published recently in Methods in Molecular Biology, the Taub Institute laboratory of Dr. Ottavio Arancio conducted a study aiming to establish an efficient and cost effective method for isolating tau protein from bacterial cells and cortices of AD patients or mice. After the final step of purification, isolated soluble tau was oligomerized, achieved via introduction of disulfide bonds. Even though the species that induced the toxicity could not be identified, Dr. Arancio’s protocol for producing tau oligomers proved to efficiently affect key features of Alzheimer’s disease, including synaptic plasticity and memory.

Ottavio Arancio, MD, PhD
Professor of Pathology and Cell Biology (in the Taub Institute)
oa1@cumc.columbia.edu





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