Dataset Information

Identification of circRNAs linked to Alzheimer's disease and related dementias.

ABSTRACT:

Introduction

Circular RNAs (circRNAs) exhibit selective expression in the brain and differential regulation in Alzheimer's disease (AD). To explore the role of circRNAs in AD, we investigated how circRNA expression varies between brain regions and with AD-related stress in human neuronal precursor cells (NPCs).

Methods

Ribosomal RNA-depleted hippocampus RNA-sequencing data were generated. Differentially regulated circRNAs in AD and related dementias were detected using CIRCexplorer3 and limma. circRNA results were validated using quantitative real-time PCR of cDNA from the brain and NPCs.

Results

We identified 48 circRNAs that were significantly associated with AD. We observed that circRNA expression differed by dementia subtype. Using NPCs, we demonstrated that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in the AD brain.

Discussion

Our study shows that differential expression of circRNA can vary by dementia subtype and brain region. We also demonstrated that circRNAs can be regulated by AD-linked neuronal stress independently from their cognate linear messenger RNAs (mRNAs).

SUBMITTER: Puri S

PROVIDER: S-EPMC10427739 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Identification of circRNAs linked to Alzheimer's disease and related dementias.

Puri Sambhavi S Hu Junming J Sun Zhuorui Z Lin Mintao M Stein Thor D TD Farrer Lindsay A LA Wolozin Benjamin B Zhang Xiaoling X

Alzheimer's & dementia : the journal of the Alzheimer's Association 20230216 8

<h4>Introduction</h4>Circular RNAs (circRNAs) exhibit selective expression in the brain and differential regulation in Alzheimer's disease (AD). To explore the role of circRNAs in AD, we investigated how circRNA expression varies between brain regions and with AD-related stress in human neuronal precursor cells (NPCs).<h4>Methods</h4>Ribosomal RNA-depleted hippocampus RNA-sequencing data were generated. Differentially regulated circRNAs in AD and related dementias were detected using CIRCexplore ...[more]

PMID: 36795937

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Project description:On March 12-14, 2024, the National Institute on Aging (NIA) together with the National Institute of Neurological Disorders and Stroke (NINDS) led a workshop exploring clinically meaningful changes in the context of Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) clinical trials (https://www.nia.nih.gov/research/dbsr/workshops/clinically-meaningful-outcomes-ad-adrd-trials). The goals were to identify research gaps, opportunities, and tools to advance patient-centered, equitable assessment of clinically meaningful change focused on biomarker status, cognition, and everyday function. The workshop fostered robust, multidisciplinary discussion between lived experience experts, advocates, researchers, clinicians, funders, payers, and regulators. The workshop addressed the criteria used to assess whether an intervention has had a clinically meaningful impact, including consideration of both benefit and harm. Here, we report on (1) criteria to consider for development, testing, and selection of clinically meaningful outcomes in AD/ADRD clinical trials; (2) methods to validate and customize clinically meaningful outcomes that are fit-for-purpose; and (3) practices that will ensure that clinically meaningful outcomes are applicable to diverse populations.HighlightsPatient-Centered Outcomes: Inclusive AD/ADRD clinical trials incorporate assessments that reflect what matters most to those impacted by these diseases, including patient- and caregiver-reported outcome measures. Culturally Relevant Assessments: There is a need for culturally sensitive and equitable assessments to better serve diverse populations in AD/ADRD research. Framework for Clinically Meaningful Change: We present a framework for defining and evaluating clinically meaningful outcomes in AD/ADRD trials, tailored to diverse stages of disease progression. Interdisciplinary Approach: We draw on insights from a multidisciplinary workshop, fostering collaboration among researchers, clinicians, and lived experience experts to advance the field.

Project description:Alzheimer's disease (AD) and related dementias (ADRD) is a complex disease with multiple pathophysiological drivers that determine clinical symptomology and disease progression. These diseases develop insidiously over time, through many pathways and disease mechanisms and continue to have a huge societal impact for affected individuals and their families. While emerging blood-based biomarkers, such as plasma p-tau181 and p-tau217, accurately detect Alzheimer neuropthology and are associated with faster cognitive decline, the full extension of plasma proteomic changes in ADRD remains unknown. Earlier detection and better classification of the different subtypes may provide opportunities for earlier, more targeted interventions, and perhaps a higher likelihood of successful therapeutic development. In this study, we aim to leverage unbiased mass spectrometry proteomics to identify novel, blood-based biomarkers associated with cognitive decline. 1,786 plasma samples from 1,005 patients were collected over 12 years from partcipants in the Massachusetts Alzheimer's Disease Research Center Longitudinal Cohort Study. Patient metadata includes demographics, final diagnoses, and clinical dementia rating (CDR) scores taken concurrently. The Proteograph™ Product Suite (Seer, Inc.) and liquid-chromatography mass-spectrometry (LC-MS) analysis were used to process the plasma samples in this cohort and generate unbiased proteomics data. Data-independent acquisition (DIA) mass spectrometry results yielded 36,259 peptides and 4,007 protein groups. Linear mixed effects models revealed 138 differentially abundant proteins between AD and healthy controls. Machine learning classification models for AD diagnosis identified potential candidate biomarkers including MBP, BGLAP, and APoD. Cox regression models were created to determine the association of proteins with disease progression and suggest CLNS1A, CRISPLD2, and GOLPH3 as targets of further investigation as potential biomarkers. The Proteograph workflow provided deep, unbiased coverage of the plasma proteome at a speed that enabled a cohort study of almost 1,800 samples, which is the largest, deep, unbiased proteomics study of ADRD conducted to date.

Project description:Currently, more than 55 million people around the world suffer from dementia, and Alzheimer's disease-related dementia (ADRD) accounts for nearly 60-70% of all those cases. The spread of AD pathology and progressive neurodegeneration in the hippocampus and cerebral cortex is strongly correlated with cognitive decline in AD patients; however, the molecular underpinning of the ADRD causality is still unclear. Studies of postmortem AD brains and animal models of AD suggest that elevated endoplasmic reticulum (ER) stress may have a role in ADRD pathology through altered neurocellular homeostasis in brain regions associated with learning and memory. To study the ER stress-associated neurocellular response and its effects on neurocellular homeostasis and neurogenesis, we modeled an ER stress challenge using Thapsigargin (TG), a specific inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), in induced pluripotent stem cell (iPSC)-derived neural stem cells (NSCs) of two individuals from our Mexican American Family Study (MAFS). High-content screening and transcriptomic analysis of the control and ER stress-challenged NSCs showed that NSC’s ER stress response resulted in a significant decline in NSC self-renewal and an increase in apoptosis and cellular oxidative stress. A total of 2300 genes were significantly (moderated t statistics FDR corrected p-value ≤ 0.05 and Fold Change absolute ≥ 2.0) differentially expressed (DE). Pathway enrichment and gene network analysis of DE genes suggests that all three unfolded protein response (UPR) pathways (PERK, IRE1, and ATF6) were significantly activated and cooperatively regulated the NSC’s transcriptional response to ER stress. Our results show that IRE1/XBP1 mediated transcriptional regulation of E2F1 and its downstream targets have a dominant role in inducing G1/S-phase cell cycle arrest in the ER stress-challenged NSCs. The ER stress-challenged NSCs also showed activation of CHOP-mediated apoptosis and dysregulation of synaptic plasticity and neurotransmitter homeostasis-associated genes. Overall, our results suggest that ER stress-associated attenuation of NSC self-renewal, increased apoptosis, and dysregulated synaptic plasticity and neurotransmitter homeostasis plausibly play a role in the causation of ADRD.

Project description:BackgroundThe ability to rate delirium severity is key to providing optimal care for persons with Alzheimer's Disease and Related Dementias (ADRD). Such ratings would allow clinicians to assess response to treatment, recovery time and prognosis, nursing burden and staffing needs, and to provide nuanced, appropriate patient-centered care. Given the lack of existing tools, we defined content domains for a new delirium severity instrument for use in individuals with mild to moderate ADRD, the DEL-S-AD.MethodsWe built upon our previous study in which we created a content domain framework to inform development of a general delirium severity instrument, the DEL-S. We engaged a new expert panel to discuss issues of measurement in delirium and dementia and to determine which content domains from the prior framework were useful in characterizing delirium severity in ADRD. We also asked panelists to identify new domains. Our panel included eight interdisciplinary members with expertise in delirium and dementia. Panelists participated in two rounds of review followed by two surveys over 2 months.ResultsPanelists endorsed the same content domains as for general delirium severity, including Cognitive, Level of Consciousness, Inattention, Psychiatric-Behavioral, Emotional Dysregulation, Psychomotor Features, and Functional; however, they excluded six of the original subdomains which they considered unhelpful in the context of ADRD: cognitive impairment; anxiety; fear/sense of unease; depression; gait/walking; and incontinence. Debated measurement challenges included assessment at one point in time versus over time, accounting for differences in clinical settings, and accurate assessment of symptoms related to delirium versus dementia.ConclusionsBy capturing a range of characteristics of delirium severity potentially present in patients with ADRD, a population that may already have attention, functional, and emotional changes at baseline, the DEL-S-AD provides a novel rating tool that will be useful for clinical and research purposes to improve patient care.

Dataset Information

Identification of circRNAs linked to Alzheimer's disease and related dementias.

Introduction

Methods

Results

Discussion

Publications

Identification of circRNAs linked to Alzheimer's disease and related dementias.

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