Miranda E. Orr
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View article: Head‐to‐head comparison of two senolytic therapies in a mouse model of tauopathy
Head‐to‐head comparison of two senolytic therapies in a mouse model of tauopathy Open
Background Tau protein accumulation induces cellular senescence in Alzheimer's disease (AD). Treating tau transgenic mice with the senolytic therapy, dasatinib plus quercetin (DQ), to clear senescent cells reduced brain pathology and impro…
View article: The Dual Role of Tau in Neuroprotection and Disease: Neuronal Senescence as a Therapeutic Target
The Dual Role of Tau in Neuroprotection and Disease: Neuronal Senescence as a Therapeutic Target Open
Background The microtubule‐associated protein tau undergoes reversible post‐translational modifications in response to various stress conditions, preserving neuronal function and stability. However, under sustained stress or pathological c…
View article: Spatial molecular characterization of early Alzheimer's disease neuropathology in aged Vervet monkeys
Spatial molecular characterization of early Alzheimer's disease neuropathology in aged Vervet monkeys Open
Background Vervets (Chlorocebus aethiops) are non‐human primates in which we previously demonstrated brain amyloid b (Ab) deposition and phosphorylated tau associations with reduced brain volume, glucose metabolism, and gait speed but lack…
View article: Thalamus has the highest density of neurescent among human brain regions
Thalamus has the highest density of neurescent among human brain regions Open
Background Cellular senescence is a complex, multi‐step process and is recognized as a contributor to neurodegenerative diseases, including Alzheimer's disease (AD). This study is focused on neurescence (i.e., senescent neurons). Analyzing…
View article: Single-cell Spatial Transcriptional Profiling Uncovers Heterogeneous Cellular Responses to Pathogenic Tau in a Mouse Model of Neurodegeneration
Single-cell Spatial Transcriptional Profiling Uncovers Heterogeneous Cellular Responses to Pathogenic Tau in a Mouse Model of Neurodegeneration Open
Summary Intracellular tau accumulation contributes to neurodegeneration and systemic dysfunction. Although tau primarily aggregates in neurons as neurofibrillary tangles (NFTs), it also affects other cell types through poorly understood me…
View article: HypoAD: volumetric and single-cell analysis reveals changes in the human hypothalamus in aging and Alzheimer’s disease
HypoAD: volumetric and single-cell analysis reveals changes in the human hypothalamus in aging and Alzheimer’s disease Open
Alterations in metabolism, stress response, sleep, circadian rhythms, and neuroendocrine processes are key features of aging and neurodegeneration. These fundamental processes are regulated by the hypothalamus, yet how its functionally dis…
View article: ZipAEr: A compressive convolutional autoencoder for high-dimensional spatial omics data at subcellular resolution
ZipAEr: A compressive convolutional autoencoder for high-dimensional spatial omics data at subcellular resolution Open
Recent advances in spatial transcriptomics have produced rich, high-throughput datasets, but their biological interpretation remains challenging due to analytical complexity. We present ZipAEr, a convolutional autoencoder tailored to extra…
View article: Building an Interdisciplinary Workforce in Geroscience: Aligning Perspectives and Educational Goals
Building an Interdisciplinary Workforce in Geroscience: Aligning Perspectives and Educational Goals Open
The National Institute on Aging-funded Geroscience Education and Training Network held the “Building an Interdisciplinary Workforce in Geroscience: Aligning Perspectives and Educational Goals” preconference workshop at the 2023 Gerontologi…
View article: Insights into pathophysiology, biomarkers, and therapeutics in tauopathies: Proceedings of the Tau2024 Global Conference
Insights into pathophysiology, biomarkers, and therapeutics in tauopathies: Proceedings of the Tau2024 Global Conference Open
Recent years have seen major advances in tau‐associated brain disorders through interdisciplinary research spanning molecular biology, neuroimaging, clinical trials, and therapeutic development. The Tau2024 Global Conference, hosted by the…
View article: Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease
Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease Open
Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer's disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures …
View article: Identification of markers for neurescence through transcriptomic profiling of postmortem human brains
Identification of markers for neurescence through transcriptomic profiling of postmortem human brains Open
Neuronal senescence (i.e., neurescent) is an important hallmark of aging and neurodegeneration, but it remains poorly characterized in the human brain due to the lack of reliable markers. This study aimed to identify neurescent markers bas…
View article: Senescent brain cell types in Alzheimer's disease: Pathological mechanisms and therapeutic opportunities
Senescent brain cell types in Alzheimer's disease: Pathological mechanisms and therapeutic opportunities Open
Cellular senescence is a cell state triggered by programmed physiological processes or cellular stress responses. Stress-induced senescent cells often acquire pathogenic traits, including a toxic secretome and resistance to apoptosis. When…
View article: Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age‐related tauopathy hippocampi
Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age‐related tauopathy hippocampi Open
INTRODUCTION Alzheimer's disease (AD), primary age‐related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p‐tau)–immunoreactive neurofibrillary degeneration, but differ in neuroanatomical …
View article: HIGH RESOLUTION SPATIAL PROTEOGENOMICS TO ASSESS TARGET ENGAGEMENT AND COMPARE SENOLYTIC EFFICACY IN THE BRAIN OF TAU TRANSGENIC MICE
HIGH RESOLUTION SPATIAL PROTEOGENOMICS TO ASSESS TARGET ENGAGEMENT AND COMPARE SENOLYTIC EFFICACY IN THE BRAIN OF TAU TRANSGENIC MICE Open
Tau protein accumulation induces cellular senescence in Alzheimer’s disease and other tauopathies contributing to dysfunction and disability. Treating tau transgenic mice with pharmacological agents to clear senescent cells, “senolytics,” …
View article: Tracing senescence in the Alzheimer’s brain through an eigengene‐based analysis of snRNA‐Seq data
Tracing senescence in the Alzheimer’s brain through an eigengene‐based analysis of snRNA‐Seq data Open
Background Cellular senescence, which can cause significant changes in morphology, metabolism, and function, is a key contributor to aging and diseases including Alzheimer’s Disease (AD). Accurate biomarker identification is essential for …
View article: Exploring Microtubule Dynamics in Alzheimer's Disease: Longitudinal Assessment Using [<sup>11</sup>C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models
Exploring Microtubule Dynamics in Alzheimer's Disease: Longitudinal Assessment Using [<sup>11</sup>C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models Open
Background Brains affected by Alzheimer's disease (AD) exhibit senile plaques containing amyloid beta (Aβ) peptides and neurofibrillary tangles, formed when tau becomes hyperphosphorylated and disengages from microtubules (MTs). Early inst…
View article: Exploring Microtubule Dynamics in Alzheimer’s Disease: Longitudinal Assessment Using [11C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models
Exploring Microtubule Dynamics in Alzheimer’s Disease: Longitudinal Assessment Using [11C]MPC‐6827 PET Imaging in APP/PS1 and PS301S Mouse Models Open
Background Brains affected by Alzheimer’s disease (AD) exhibit senile plaques containing amyloid beta (Aß) peptides and neurofibrillary tangles, formed when tau becomes hyperphosphorylated and disengages from microtubules (MTs). Early inst…
View article: Spatial proteome profiling for distinguishing tangle‐bearing neurons and their microenvironments from healthy neurons in Alzheimer’s disease brains
Spatial proteome profiling for distinguishing tangle‐bearing neurons and their microenvironments from healthy neurons in Alzheimer’s disease brains Open
Background An important hallmark of Alzheimer’s Disease (AD) is the presence of neurofibrillary tangles (NFTs) composed of phosphorylated tau, which are commonly assessed using AT8 immunostains. Identifying additional markers to characteri…
View article: PET Imaging of Microtubules in Cognitively Impaired and Normal Older Adults
PET Imaging of Microtubules in Cognitively Impaired and Normal Older Adults Open
Background Although associated with early changes in Aβ and tau formations, microtubule (MT) destabilization has not yet been systematically evaluated as an early biomarker of neurodegeneration and a tool to quantify it in real‐time could …
View article: Upregulation of adenosine A2A receptor by astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits.
Upregulation of adenosine A2A receptor by astrocytes is sufficient to trigger hippocampal multicellular dysfunctions and memory deficits. Open
Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A1 (A1R) and A2A (A2AR) receptors. Interestingly…
View article: Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [<sup>11</sup>C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology
Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [<sup>11</sup>C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology Open
INTRODUCTION Microtubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aβ) and tau‐based degenerative events and early changes in presymptomatic Alzheimer's …
View article: An interpretable machine learning‐based cerebrospinal fluid proteomics clock for predicting age reveals novel insights into brain aging
An interpretable machine learning‐based cerebrospinal fluid proteomics clock for predicting age reveals novel insights into brain aging Open
Machine learning can be used to create “biologic clocks” that predict age. However, organs, tissues, and biofluids may age at different rates from the organism as a whole. We sought to understand how cerebrospinal fluid (CSF) changes with …
View article: Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer’s Disease
Evaluation of Exploratory Fluid Biomarker Results from a Phase 1 Senolytic Trial in Mild Alzheimer’s Disease Open
Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome me…
View article: Focus on senescence: Clinical significance and practical applications
Focus on senescence: Clinical significance and practical applications Open
The older population is increasing worldwide, and life expectancy is continuously rising, predominantly thanks to medical and technological progress. Healthspan refers to the number of years an individual can live in good health. From a ge…