MicroRNA Profile in Patients with Alzheimer’s Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples

Riancho, Javier; Vázquez-Higuera, José Luis; Pozueta, Ana; Lage, Carmen; Kazimierczak, Martha; Bravo, María Mercedes; Calero, Miguel; Gonalezález, Andrea; Rodríguez, Eloy Rodríguez; Lleó, Alberto; Sánchez‐Juan, Pascual

doi:10.3233/jad-161179

Cited by 140 publications

(83 citation statements)

References 31 publications

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“…Recent studies have demonstrated the usefulness of this novel biomarker technology for prognosis as well as biological mechanisms for AD in the general population (Paschon et al 2016; Rajendran et al 2006; Riancho et al 2017; Sharples et al 2008; Vingtdeux et al 2012; Xiao et al 2017; Yuyama and Igarashi 2017), and can also be used for studying the propagation of pathology within the brain (Polanco et al 2016; Winston et al 2016). We are hopeful that this novel methodology can shed light on early events in the pathology in DS-AD and hopefully lead to novel intervention or prevention therapies.…”

Section: Discussionmentioning

confidence: 99%

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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Every person with Down syndrome (DS) has the characteristic features of Alzheimer’s disease (AD) neuropathology in their brain by the age of forty, and most go on to develop AD dementia. Since people with DS show highly variable levels of baseline function, it is often difficult to identify early signs of dementia in this population. The discovery of blood biomarkers predictive of dementia onset and/or progression in DS is critical for developing effective clinical diagnostics. Our recent studies show that neuron-derived exosomes, which are small extracellular vesicles secreted by most cells in the body, contain elevated levels of amyloid-beta peptides and phosphorylated-Tau that could indicate a preclinical AD phase in people with DS starting in childhood. We also found that the relative levels of these biomarkers were altered following dementia onset. Exosome release and signaling are dependent on cellular redox homeostasis as well as on inflammatory processes, and exosomes may be involved in the immune response, suggesting a dual role as both triggers of inflammation in the brain and propagators of inflammatory signals between brain regions. Based on recently reported connections between inflammatory processes and exosome release, the elevated neuroinflammatory state observed in people with DS may affect exosomal AD biomarkers. Herein, we discuss findings from studies of people with DS, people with DS and AD (DS-AD), and mouse models of DS showing new connections between neuroinflammatory pathways, oxidative stress, exosomes, and exosome-mediated signaling, which may inform future AD diagnostics, preventions, and treatments in the DS population as well as in the general population.

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Section: Discussionmentioning

confidence: 99%

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Hamlett

Ledreux

Potter³

et al. 2018

Free Radical Biology and Medicine

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“…Tenth, our data implicate that JC1 may be useful to assess brain integrity. But other exosomes presenting in CSF may be also important to confer disease pathology 23–25 . How specifically CSF mitochondrial function reflects brain pathological state remain to be fully addressed.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage

Chou

Lan

Esposito

et al. 2017

Stroke

104

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Background and Purpose Recent studies suggest that extracellular mitochondria may be involved in the pathophysiology of stroke. In this study, we assessed the functional relevance of endogenous extracellular mitochondria in cerebrospinal fluid (CSF) in rats and humans after subarachnoid hemorrhage (SAH). Methods A standard rat model of SAH was used, where an intraluminal suture was used to perforate a cerebral artery, thus leading to blood extravasation into subarachnoid space. At 24 and 72 hrs post-SAH, neurological outcomes were measured, and the standard JC1 assay was used to quantify mitochondrial membrane potentials in the CSF. To further support the rat model experiments, CSF samples were obtained from 41 SAH patients and 27 control subjects. Mitochondrial membrane potentials were measured with the JC1 assay, and correlations with clinical outcomes were assessed at 3 months. Results In the standard rat model of SAH, extracellular mitochondria was detected in CSF at 24 and 72 hrs after injury. JC1 assays demonstrated that mitochondrial membrane potentials in CSF were decreased after SAH compared with sham-operated controls. In human CSF samples, extracellular mitochondria were also detected, and JC1 levels were also reduced after SAH. Furthermore, higher mitochondrial membrane potentials in the CSF was correlated with good clinical recovery at 3 months after SAH onset. Conclusions This proof-of-concept study suggests that extracellular mitochondria may provide a “biomarker-like” glimpse into brain integrity and recovery after injury.

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“…While there are no reports of the effect of central mir-598-3p on learning in the literature, mir-598-3p is downregulated in the cerebrospinal fluid of patients diagnosed with Alzheimer's disease [41]. Given that Alzheimer's is associated with significant memory impairment as the disease progresses, this is consistent with upregulated mir-598-3p in SS mice without retrieval being associated with an enhanced fear memory.…”

Section: Discussionmentioning

confidence: 54%

microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

Jones

Sillivan

Jamieson

et al. 2019

Preprint

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Number of words in abstract: 214Number of words in main text: 5,913Running title: BLA mir-598-3p supports stress-enhanced memory ABSTRACT microRNAs (miRNAs) have emerged as potent regulators of learning, recent memory and extinction. However, our understanding of miRNAs directly involved in regulating complex psychiatric conditions perpetuated by aberrant memory, such as in posttraumatic stress disorder (PTSD), remains limited. To begin to address the role of miRNAs in persistent memory, we performed small-RNA sequencing on basolateral amygdala (BLA) tissue to identify miRNAs altered by auditory fear conditioning (FC) one month after training. mir-598-3p, a highly conserved miRNA previously unstudied in the brain, was downregulated in the BLA. Further decreasing BLA mir-598-3p levels did not alter the expression or extinction of the remote fear memory. Given that stress is a critical component in PTSD, we next assessed the impact of stress-enhanced fear learning (SEFL) on mir-598-3p levels, finding the miRNA is elevated in the BLA of male, but not female, mice susceptible to the effects of stress in SEFL. Accordingly, intra-BLA inhibition of mir-598-3p interfered with expression and extinction of the remote fear memory in male, but not female, mice. This effect could not be attributed to an anxiolytic effect of miRNA inhibition. Finally, bioinformatic analysis following quantitative proteomics on BLA tissue collected 30 days post-SEFL training identified putative mir-598-3p targets and related pathways mediating the differential susceptibility, with evidence for regulation of the actin cytoskeleton.

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MicroRNA Profile in Patients with Alzheimer’s Disease: Analysis of miR-9-5p and miR-598 in Raw and Exosome Enriched Cerebrospinal Fluid Samples

Cited by 140 publications

References 31 publications

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Exosomal biomarkers in Down syndrome and Alzheimer's disease

Extracellular Mitochondria in Cerebrospinal Fluid and Neurological Recovery After Subarachnoid Hemorrhage

microRNA mir-598-3p mediates susceptibility to stress-enhancement of remote fear memory

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