Taub Institute: Genomics Core
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TaubCONNECT Research Perspectives:
May 2021

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April 2021:

Association Between Early Psychotic Symptoms and Alzheimer's Disease Prognosis in a Community-Based Cohort

Complexity and Graded Regulation of Neuronal Cell-Type-Specific Alternative Splicing Revealed by Single-Cell RNA Sequencing

The Microtubule Cytoskeleton at the Synapse & The Synaptic Life of Microtubules

Distinct Cortical Thickness Patterns Link Disparate Cerebral Cortex Regions to Select Mobility Domains

March 2021:

Optimizing Subjective Cognitive Decline to Detect Early Cognitive Dysfunction

The AD Tau Core Spontaneously Self-Assembles and Recruits Full-Length Tau to Filaments

Olfactory Impairment is Related to Tau Pathology and Neuroinflammation in Alzheimer's Disease

Race/ethnicity and Gender Modify the Association Between Diet and Cognition in U.S. Older Adults: National Health and Nutrition Examination Survey 2011-2014

Insights Into the Role of Diet and Dietary Flavanols in Cognitive Aging: Results of a Randomized Controlled Trial

February 2021:

Plasma P-Tau181, P-Tau217, and Other Blood-Based Alzheimer's Disease Biomarkers in a Multi-Ethnic, Community Study

Pathogenic Role of Delta 2 Tubulin in Bortezomib-Induced Peripheral Neuropathy

November 2020:

Association of APOE E2 Genotype with Alzheimer's and Non-Alzheimer's Neurodegenerative Pathologies

APOE Ī•4 and Resting-State Functional Connectivity in Racially/Ethnically Diverse Older Adults

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults

Alzheimer-Related Altered White Matter Microstructural Integrity in Down Syndrome: a Model for Sporadic AD?

October 2020:

Chemogenetic attenuation of neuronal activity in the entorhinal cortex reduces AĪ² and tau pathology in the hippocampus

Alzheimer-Related Cerebrovascular Disease in Down Syndrome

Depression is Associated With Preserved Cortical Thickness Relative to Apathy in Frontotemporal Dementia

July 2020:

Endothelial Activation of Caspase-9 Promotes Neurovascular Injury in Retinal Vein Occlusion

Proteomic Profiles for Alzheimer's Disease and Mild Cognitive Impairment Among Adults with Down Syndrome Spanning Serum and Plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) Study

Cognitive Tests aid in Clinical Differentiation of Alzheimer's Disease Versus Alzheimer's Disease with Lewy Body Disease: Evidence from a Pathological Study

June 2020:

Tau is not Necessary for Amyloid-Beta-Induced Synaptic and Memory Impairments

IL-27: An Endogenous Constitutive Repressor of Human Monocytes

Subgingival Microbiome and Clinical Periodontal Status in an Elderly Cohort: The WHICAP Ancillary Study of Oral Health

May 2020:

"Everything Hurts!" Distress in Semantic Variant Primary Progressive Aphasia

Metabolic Correlates of Prevalent Mild Cognitive Impairment and Alzheimer's Disease in Adults with Down Syndrome

Down Syndrome: Distribution of Brain Amyloid in Mild Cognitive Impairment

April 2020:

Cortical Thickness and its Associations with Age, Total Cognition and Education Across the Adult Lifespan

Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers

Phospholipase D1 Ablation Disrupts Mouse Longitudinal Hippocampal Axis Organization and Functioning

March 2020:

Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Profilin 1 Delivery Tunes Cytoskeletal Dynamics Toward CNS Axon Regeneration

Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls Across Multiple Cohorts

February 2020:

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

Exceptionally Low Likelihood of Alzheimerā€™s Dementia in APOE2 Homozygotes from a 5,000-Person Neuropathological Study

January 2020:

Microglial Activation, but not Tau Pathology, is Independently Associated with Amyloid Positivity and Memory Impairment

CRISPR/Cas9 Editing of APP C-Terminus Attenuates β-Cleavage and Promotes α-Cleavage

December 2019:

Activity-Dependent Nucleation of Dynamic Microtubules at Presynaptic Boutons Controls Neurotransmission

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

Sleep Fragmentation, Microglial Aging, and Cognitive Impairment in Adults with and Without Alzheimer's Dementia

November 2019:

First Place: Studying Biochemical Mechanisms of Protective Gene Variants in Isogenic Stem Cell-derived Early Onset Alzheimerā€™s Disease Models

First Place: Glial Heterogeneity in Normal Human Cortex and Huntington Disease Interrogated Through Single Cell Nuclear RNA Sequencing

October 2019:

Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

Promotion of Axon Growth by the Secreted End of a Transcription Factor

September 2019:

Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume

Synaptic and Memory Dysfunction Induced by Tau Oligomers is Rescued by up-regulation of the Nitric Oxide Cascade

Medicaid Contributes Substantial Costs to Dementia Care in an Ethnically Diverse Community Population

August 2019:

Neuroinflammation in Frontotemporal Lobar Degeneration Revealed by 11Cā€PBR28 PET

Live Imaging of ESCRT Proteins in Microfluidically Isolated Hippocampal Axons

July 2019:

Alzheimer's Association International Conference (AAIC 2019)

June 2019:

CpGā€Related SNPs in the MS4A Region Have a Doseā€Dependent Effect on Risk of Lateā€“Onset Alzheimer Disease

MFN2 Mutations in Charcotā€“Marieā€“Tooth Disease Alter Mitochondria-Associated ER Membrane Function but Do Not Impair Bioenergetics

May 2019:

Association of Variants in PINX1 and TREM2 With Late-Onset Alzheimer Disease

Brain Biomarkers and Cognition Across Adulthood

April 2019:

Predicting Cognitive Improvement in Normal Pressure Hydrocephalus Patients Using Preoperative Neuropsychological Testing and Cerebrospinal Fluid Biomarkers

Brain Arterial Dilatation and the Risk of Alzheimer's Disease

March 2019:

Elevated Cellular Cholesterol in Familial Alzheimer's Presenilin 1 Mutation is Associated with Lipid Raft Localization of Ī²-Amyloid Precursor Protein

FDG-PET Patterns Associated with Underlying Pathology in Corticobasal Syndrome

February 2019:

Effect of Aerobic Exercise on Cognition in Younger Adults: A Randomized Clinical Trial

Exercise-linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimerā€™s Models

January 2019:

A Tau Homeostasis Signature Is Linked with the Cellular and Regional Vulnerability of Excitatory Neurons to Tau Pathology

Between-network Functional Connectivity Is Modified by Age and Cognitive Task Domain

December 2018:

Epigenome-Wide Study Uncovers Large-Scale Changes in Histone Acetylation Driven by Tau Pathology in Aging and Alzheimerā€™s Human Brains

Semantic Network Function Captured by Word Frequency in Nondemented APOE Īµ4 Carriers

November 2018:

First Place: NSUN2 is Dysregulated in Alzheimer's Disease

First Place: High-throughput Disease Modeling to Uncover Shared and Unique Characteristics Among Neurodegenerative Diseases

October 2018:

Homeostatic Plasticity Scales Dendritic Spine Volumes and Changes the Threshold and Specificity of Hebbian Plasticity

An MRI Measure of Degenerative and Cerebrovascular Pathology in Alzheimer Disease

Integrative Transcriptome Analyses of the Aging Brain Implicate Altered Splicing in Alzheimer's Disease Susceptibility

September 2018:

Clinical Experience with Cerebrospinal Fluid AĪ²42, Total and Phosphorylated Tau in the Evaluation of 1,016 Individuals for Suspected Dementia

Evaluation of TDP-43 Proteinopathy and Hippocampal Sclerosis in Relation to APOE Īµ4 Haplotype Status: A Community-Based Cohort Study

August 2018:

A Multi-Omic Atlas of the Human Frontal Cortex for Aging and Alzheimer's Disease Research

An Alzheimer's Linked Loss-of-Function CLN5 Variant Impairs Cathepsin D Maturation Consistent with a Retromer Trafficking Defect

Letter and Category Fluency Performance Correlates with Distinct Patterns of Cortical Thickness in Older Adults

July 2018:

Activating Transcription Factor 4 (ATF4) Regulates Neuronal Activity by Controlling GABABR Trafficking

Whole-exome Sequencing in 20,197 Persons for Rare Variants in Alzheimer's Disease

June 2018:

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

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

May 2018:

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

Oligomeric AĪ²1-42 Triggers the Generation of a Retrograde Signaling Complex from Sentinel mRNAs in Axons

April 2018:

Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein

Medical Retirement from Sport after Concussions: A Practical Guide for a Difficult Discussion

March 2018:

Cross Domain Self-Monitoring in Anosognosia for Memory Loss in Alzheimer's Disease

White Matter Changes in Alzheimer's Disease: A Focus on Myelin and Oligodendrocytes

February 2018:

ZCCHC17 is a Master Regulator of Synaptic Gene Expression in Alzheimer's Disease

Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia

A Transcriptomic Atlas of Aged Human Microglia

January 2018:

Neuronal Lysosomal Dysfunction Releases Exosomes Harboring APP C-terminal Fragments and Unique Lipid Signatures

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

PAC1 Receptorā€“Mediated Clearance of Tau in Postsynaptic Compartments Attenuates Tau Pathology in Mouse Brain

Natura Myeku, PhD

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimerā€™s disease (AD) and correlates with cognitive decline in patients with AD. In normal conditions, tau is cytosolic axonal protein that stabilizes microtubules, and its level in synapses is low. Under disease conditions, however, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, a new study by Dr. Natura Myeku, first author Ari Schaler, and colleagues from Taub separated synapses into pre- and postsynaptic compartments to show that, in AD brains, synaptic tau accumulates predominantly in the postsynaptic compartments, making these structures vulnerable to tau toxicity. As recently reported in Science Translational Medicine and featured on CUIMC Newsroom, these postsynaptic compartments contained not only a higher amount of tau, but the tau contained was more pathogenic, acting as a seed to recruit naĆÆve tau into aggregates.

Alzheimerā€™s disease

Figure: A, B) In Alzheimerā€™s disease, seed-competent synaptic tau accumulates predominately in the post-synaptic compartment contributing to synaptic dyshomeostasis. C, D) Receptor-mediated clearance of tau in the post-synaptic compartment by the local proteasomes could be a new approach to protect synapses from toxic tau.

Previous research by Dr. Myeku and colleagues has shown that tau aggregation in mice can be attenuated by enhancing the clearance of tau via proteasome machinery. Thus, to combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, the investigators targeted a receptor situated on the surface of postsynaptic compartments, stimulating the pituitary adenylate cyclaseā€“activating polypeptide (PACAP) type 1 receptor (PAC1R). Mice with early-stage tau pathology treated with PACAP exhibited reduced postsynaptic tau, reduced hyperphosphorylated synaptic tau, and overall attenuated tauopathy. In addition, these rTg4510 transgenic mice demonstrated improved cognitive performance on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.

Natura Myeku, PhD
Assistant Professor of Pathology and Cell Biology (in the Taub Institute)

Socioeconomic and Psychosocial Mechanisms Underlying Racial/Ethnic Disparities in Cognition Among Older Adults

Laura Zahodne, PhD     Adam M. Brickman, PhD

Non-Hispanic Black and Hispanic older adults experience disproportionate burden of Alzheimerā€™s disease and related dementias (ADRD) compared with non-Hispanic Whites. Substantial research indicates that these racial/ethnic differences in ADRD risk and prevalence reflect health inequalities that are avoidable, unnecessary, and unjust. Socioeconomic factors, such as educational attainment and income, clearly contribute to ADRD inequalities, but these variables fail to fully explain group differences. An emerging literature highlights other modifiable psychosocial factors that contribute to racial/ethnic differences in ADRD risk above and beyond socioeconomic factors, such as racial discrimination.

Mediation Model
Figure 1. Mediation Model. Significant Paths are Shown as Black Lines, With Corresponding Standardized Parameter Estimates and Standard Errors.Nonsignificant Paths are Depicted With Gray, Dotted Lines. For Simplicity, Direct Effects, Covariates (i.e., Age and Sex/Gender) and Covariances Between Mediators are Not Shown.

Recently, a battery of psychosocial measures was added to the long-running Washington Heights-Inwood Columbia Aging Project in order to more fully identify factors that create and sustain racial/ethnic inequalities in ADRD. As reported in Neuropsychology, Drs. Laura Zahodne, Adam Brickman, and colleagues from Taub, Neurology, and the University of Michigan used mediation analyses to quantify the proportion of Black-White and Hispanic-White disparities in late-life cognitive performance explained by various social determinants of health. They found that socioeconomic factors (i.e., educational attainment, income) explained approximately 50% of cognitive disparities. An additional 5-8% of disparities were explained by external locus of control, as measured by individualsā€™ self-reported perceptions of outside constraints that limit their ability to achieve important life outcomes. While there were also racial/ethnic differences on a commonly-used measure of everyday discrimination such that Black older adults reported more frequent discrimination than Hispanics or Whites, everyday discrimination was not uniquely associated with cognitive performance.

These results suggest that external locus of control may be an under-recognized contributor to ADRD inequalities. As an individual-level indicator of chronic institutional and interpersonal marginalization, external locus of control may represent not only an upstream determinant of known drivers of health disparities (e.g., economic opportunity) but also an independent driver of disparities that could operate via stress and/or other biopsychosocial pathways.

Laura B. Zahodne, PhD
Adjunct Associate Research Scientist (in Neurology and the Taub Institute)
Assistant Professor of Psychology, University of Michigan

Recognition Memory and Divergent Cognitive Profiles in Prodromal Genetic Frontotemporal Dementia

Megan S. Barker, PhD    Stephanie Cosentino, PhD
Megan S. Barker, PhD    Stephanie Cosentino, PhD

Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative disease that primarily affects personality and behavior. Executive dysfunction, that is deficits in higher-order cognitive skills such as judgment and reasoning, is typically considered the cognitive hallmark of bvFTD. However, recent research has shown that episodic memory deficits, which are more prototypical of Alzheimerā€™s disease than bvFTD, may also be present in up to 50% of bvFTD patients. Furthermore, there is some evidence that episodic memory deficits may be more common in carriers of a MAPT genetic mutation, which is a specific type of tau mutation that causes bvFTD, compared with other bvFTD-causing genetic mutations (C9orf72, GRN). Whether episodic memory deficits are detectable at the earliest symptomatic (ā€œprodromalā€) stage of disease, and whether there are differences between genetic mutation carrier groups at this prodromal disease stage, remains largely unexamined in the literature.

cortex figure
Figure. Bar plots showing mean performance on memory and other cognitive tests, compared across genetic carrier (MAPT, GRN, C9orf72) and non-carrier control groups. Descriptive only (uncorrected). Error bars represent 95% confidence intervals. Raw data depicted in gray.

In a study recently published in the journal Cortex, Drs. Stephanie Cosentino, Ted Huey, and colleagues, including postdoctoral research scientist and lead author Dr. Megan Barker, investigated patterns of episodic memory and cognitive impairment in prodromal bvFTD. Specifically, they sought to understand the extent to which difficulty recognizing words from a previously learned list reflected impairment in memory storage per se, versus impairment in semantic (language) or executive functioning, which are the cognitive domains more classically associated with bvFTD. Leveraging data from 57 carriers of a pathogenic variant of the MAPT (N = 23), GRN (N = 15), or C9orf72 (N = 19) genes, who will go on to develop bvFTD in the future but were exhibiting very mild symptoms at the time of the study, the authors reported that episodic memory dysfunction is detectable in prodromal bvFTD. That is, the patient group was less successful at recognizing words from the target list than controls. Of the genetic groups, this deficit was most reliably observed in MAPT and GRN mutation carriers. However, in MAPT carriers, the episodic memory weakness appeared to reflect a genuine memory difficulty, as well as a semantic (language) disruption, while, in contrast, the memory problems in GRN carriers seemed to be underpinned by executive dysfunction. Episodic memory was most preserved in the C9orf72 group, but processing speed was mildly slowed in this group as compared to controls. Overall, these results suggest that distinct cognitive weaknesses are evident in carriers of the three disease-causing genes during the prodromal disease stage, and may differentially contribute to poor performance on episodic memory tests.

Megan S. Barker, PhD
Postdoctoral Research Scientist (in the Taub Institute)

Stephanie Cosentino, PhD
Associate Professor of Neuropsychology (in Neurology, the Sergievsky Center, and the Taub Institute)

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