scholarly journals Gender-Dependent Deregulation of Linear and Circular RNA Variants of HOMER1 in the Entorhinal Cortex of Alzheimer’s Disease

2021 ◽  
Vol 22 (17) ◽  
pp. 9205
Author(s):  
Amaya Urdánoz-Casado ◽  
Javier Sánchez-Ruiz de Gordoa ◽  
Maitane Robles ◽  
Blanca Acha ◽  
Miren Roldan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Circular Rna ◽  
Brain Regions ◽  
Mrna Levels ◽  
C Protein ◽  
Amyloid Aβ ◽  
Cortical Regions ◽  
Female Specific

The HOMER1 gene is involved in synaptic plasticity, learning and memory. Recent studies show that circular RNA derived from HOMER1 (circHOMER1) expression is altered in some Alzheimer’s disease (AD) brain regions. In addition, HOMER1 messenger (mRNA) levels have been associated with β-Amyloid (Aβ) deposits in brain cortical regions. Our aim was to measure the expression levels of HOMER1 circRNAs and their linear forms in the human AD entorhinal cortex. First, we showed downregulation of HOMER1B/C and HOMER1A mRNA and hsa_circ_0006916 and hsa_circ_0073127 levels in AD female cases compared to controls by RT-qPCR. A positive correlation was observed between HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073128 with HOMER1B/C protein only in females. Global average area of Aβ deposits in entorhinal cortex samples was negatively correlated with HOMER1B/C, HOMER1A mRNA, and hsa_circ_0073127 in both genders. Furthermore, no differences in DNA methylation were found in two regions of HOMER1 promoter between AD cases and controls. To sum up, we demonstrate that linear and circular RNA variants of HOMER1 are downregulated in the entorhinal cortex of female patients with AD. These results add to the notion that HOMER1 and its circular forms could be playing a female-specific role in the pathogenesis of AD.

scholarly journals Linking the association between circRNAs and Alzheimer’s disease progression by multi-tissue circular RNA characterization

2020 ◽  
Author(s):  
IJu Lo ◽  
Jamie Hill ◽  
Bjarni J. Vilhjálmsson ◽  
Jørgen Kjems
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inferior Frontal Gyrus ◽  
Circular Rna ◽  
Brain Regions ◽  
Parahippocampal Gyrus ◽  
Circular Rnas ◽  
Cognitive Disability ◽  
Anterior Prefrontal Cortex ◽  
Progressive Course

AbstractAlzheimer’s Disease (AD) has devastating consequences for patients during its slow, progressive course. It is important to understand the pathology of AD onset. Recently, circular RNAs (circRNAs) have been found to participate in many human diseases including cancers and neurodegenerative conditions. In this study, we mined the published dataset on the AMP-AD Knowledge Portal from the Mount Sinai Brain Bank (MSBB) to describe the circRNA profiles at different AD stage in brain samples from four AD patients brain regions, anterior prefrontal cortex, superior temporal lobe, parahippocampal gyrus, and inferior frontal gyrus. We found in total 147 circRNAs to be differentially expressed (DE) during AD progression in the four regions. We also characterized the mRNA-circRNA co-expression network and annotated the potential function of circRNAs based on the co-expressed modules. Based on our results, we propose that parahippocampal gyrus is the most circRNA-regulated region during the AD progression. The strongest negatively AD stage-correlated module in parahippocampal gyrus were enriched in cognitive disability and pathological-associated pathways such as synapse organization and regulation of membrane potential. Finally, the regression model based on the expression pattern of DE circRNAs in the module could help to distinguish the disease severity of patients, further supported the importance of circRNAs in AD pathology. In conclusion, our finding indicates that circRNAs in parahippocampal gyrus are possible regulators of AD progression and potentially be a therapeutic target or of AD.

scholarly journals Following spatial Aβ aggregation dynamics in evolving Alzheimer’s disease pathology by imaging stable isotope labeling kinetics

2021 ◽  
Vol 7 (25) ◽  
pp. eabg4855
Author(s):  
Wojciech Michno ◽  
Katie M. Stringer ◽  
Thomas Enzlein ◽  
Melissa K. Passarelli ◽  
Stephane Escrig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mass Spectrometry Imaging ◽  
Isotope Labeling ◽  
Brain Regions ◽  
Plaque Development ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Detailed Picture

β-Amyloid (Aβ) plaque formation is the major pathological hallmark of Alzheimer’s disease (AD) and constitutes a potentially critical, early inducer driving AD pathogenesis as it precedes other pathological events and cognitive symptoms by decades. It is therefore critical to understand how Aβ pathology is initiated and where and when distinct Aβ species aggregate. Here, we used metabolic isotope labeling in APPNL-G-F knock-in mice together with mass spectrometry imaging to monitor the earliest seeds of Aβ deposition through ongoing plaque development. This allowed visualizing Aβ aggregation dynamics within single plaques across different brain regions. We show that formation of structurally distinct plaques is associated with differential Aβ peptide deposition. Specifically, Aβ1-42 is forming an initial core structure followed by radial outgrowth and late secretion and deposition of Aβ1-38. These data describe a detailed picture of the earliest events of precipitating amyloid pathology at scales not previously possible.

scholarly journals Sex-stratified single-cell RNA-Seq analysis identifies sex-specific and cell type-specific transcriptional responses in Alzheimer’s disease across two brain regions.

2021 ◽  
Author(s):  
Stella Belonwu ◽  
Yaqiao Li ◽  
Daniel Bunis ◽  
Arjun Rao ◽  
Caroline Warly Solsberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Entorhinal Cortex ◽  
Neurodegenerative Disorder ◽  
Brain Regions ◽  
Specific Gene ◽  
Cell Type ◽  
Transcriptional Responses ◽  
Cell Type Specific

Abstract Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder that disproportionately affects women. Since neural anatomy and disease pathophysiology differ by sex, investigating sex-specific mechanisms in AD pathophysiology can inform new therapeutic approaches for both sexes. Here, we utilized nearly 74,000 cells from human prefrontal and entorhinal cortex samples from the first two publicly available single-cell RNA sequencing AD datasets to study cell type-specific sex-stratified transcriptomic perturbations in AD. Our examination at the single-cell level revealed that sex-specific gene and pathway differences in AD were most prominently observed in glial cells of the prefrontal cortex. In the entorhinal cortex, we observed the same genes and pathways to be perturbed in opposing directions between sexes in AD relative to healthy state. Our findings contribute to growing evidence of sex differences in AD-related transcriptomic changes, which can fuel the development of therapies that may prove more effective at reversing AD pathophysiology.

scholarly journals Neuropathology of Aging in Cats and its Similarities to Human Alzheimer’s Disease

2021 ◽  
Vol 2 ◽  
Author(s):  
Lorena Sordo ◽  
Alessandra C. Martini ◽  
E. Fiona Houston ◽  
Elizabeth Head ◽  
Danièlle Gunn-Moore
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Brain Regions ◽  
Hyperphosphorylated Tau ◽  
Age Related ◽  
Cat Brain ◽  
Amyloid Aβ ◽  
Intraneuronal Aβ

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

scholarly journals A meta-analysis of brain DNA methylation across sex, age and Alzheimer’s disease points for accelerated epigenetic aging in neurodegeneration

2020 ◽  
Author(s):  
C Pellegrini ◽  
C Pirazzini ◽  
C Sala ◽  
L Sambati ◽  
I Yusipov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Meta Analysis ◽  
Brain Regions ◽  
Epigenetic Aging ◽  
High Concordance ◽  
Males And Females ◽  
Cortical Regions ◽  
The Brain

AbstractAlzheimer’s disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in the brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of 4 brain regions (temporal, frontal, entorhinal cortex and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age- and AD-associated epigenetic profiles. We showed that DNAm differences between males and females tend to be shared between the 4 brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation changes also during aging is higher than expected, but that differences between males and females tend to be maintained, with only few probes showing sex-by-age interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm changes with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease.In conclusion, we demonstrated that age-associated, but not sex-associated DNAm concurs to the epigenetic deregulation observed in AD, providing new insight on how advanced age enables neurodegeneration.

scholarly journals AstroDot: a new method for studying the spatial distribution of mRNA in astrocytes

2019 ◽  
Author(s):  
Marc Oudart ◽  
Romain Tortuyaux ◽  
Philippe Mailly ◽  
Noémie Mazaré ◽  
Anne-Cécile Boulay ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Large Subunit ◽  
Three Dimensional ◽  
R Package ◽  
New Method ◽  
Mrna Levels ◽  
Model Of Alzheimer’S Disease ◽  
Confocal Images ◽  
Amyloid Aβ

AbstractCells with a complex shape often use mRNA distribution and local translation to regulate distal functions. These mechanisms have recently been described in astrocytes, the processes of which contact and functionally modulate neighbouring synapses and blood vessels. In order to study the distribution of mRNA in astrocytes, we developed a three-dimensional histological method that combines mRNA detection viain situhybridization with immunostaining of the astrocyte-specific intermediate filament glial fibrillary acidic protein (GFAP). Three-dimensional confocal images were analyzed using AstroDot, a custom Image J plug-in developed in-house for the identification and quantification of mRNAs in GFAP-immunolabelled astrocyte somata, large processes and fine processes. The custom R package AstroStat was used to analyze the AstroDot results. Taking the characterization of mRNAs encoding the astrocyte-specific GFAP α and δ isoforms in the hippocampus as a proof of concept, we showed thatGfapα andGfapδ mRNAs mainly colocalized with GFAP in astrocyte processes.Gfapα mRNA was more abundant thanGfapδ mRNA, and was predominantly found in fine processes. Upon glial activation in the APPswe/PS1dE9 mouse model of Alzheimer’s disease, the same overall patterns were found but we noted strong variations inGfapα andGfapδ mRNA density and distribution as a function of the part of the hippocampus and the astrocyte’s proximity to beta-amyloid (Aβ) plaques. In astrocytes not associated with Aβ, Gfap α mRNA levels were only slightly elevated, and Gfap δ mRNA was distributed within the fine processes; these effects were more prominent in CA3 than in CA1. In contrast, levels of both mRNAs were markedly elevated in the fine processes of Aβ-associated astrocytes in both CA1 and CA3. In order to validate our new method, we confirmed thatRpl4mRNA (a ubiquitously expressed mRNA encoding the large subunit ribosomal protein 4) was present in large and fine processes in both astrocytes and microglia. In summary, we have developed a novel, reliable set of tools for characterizing mRNA densities and distributions in the somata and processes of astrocytes and microglia in physiological or pathological settings. Furthermore, our results suggest that intermediate filaments are crucial for distributing mRNA within astrocytes and for modulating specificGfapmRNA profiles in Alzheimer’s disease.

scholarly journals EEG Window Length Evaluation for the Detection of Alzheimer’s Disease over Different Brain Regions

2019 ◽  
Vol 9 (4) ◽  
pp. 81 ◽  
Author(s):  
Katerina D. Tzimourta ◽  
Nikolaos Giannakeas ◽  
Alexandros T. Tzallas ◽  
Loukas G. Astrakas ◽  
Theodora Afrantou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Spectral Features ◽  
Classification Problems ◽  
Whole Brain ◽  
Central Regions ◽  
Eeg Recordings ◽  
Cortical Regions ◽  
The Right

Alzheimer’s Disease (AD) is a neurogenerative disorder and the most common type of dementia with a rapidly increasing world prevalence. In this paper, the ability of several statistical and spectral features to detect AD from electroencephalographic (EEG) recordings is evaluated. For this purpose, clinical EEG recordings from 14 patients with AD (8 with mild AD and 6 with moderate AD) and 10 healthy, age-matched individuals are analyzed. The EEG signals are initially segmented in nonoverlapping epochs of different lengths ranging from 5 s to 12 s. Then, a group of statistical and spectral features calculated for each EEG rhythm (δ, θ, α, β, and γ) are extracted, forming the feature vector that trained and tested a Random Forests classifier. Six classification problems are addressed, including the discrimination from whole-brain dynamics and separately from specific brain regions in order to highlight any alterations of the cortical regions. The results indicated a high accuracy ranging from 88.79% to 96.78% for whole-brain classification. Also, the classification accuracy was higher at the posterior and central regions than at the frontal area and the right side of temporal lobe for all classification problems.

scholarly journals Selective Vulnerability of Neurons in Layer II of the Entorhinal Cortex during Aging and Alzheimer's Disease

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Alexis M. Stranahan ◽  
Mark P. Mattson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Entorhinal Cortex ◽  
Selective Vulnerability ◽  
Brain Regions ◽  
System Level ◽  
Molecular Alterations ◽  
Age Related ◽  
Existing Data ◽  
Biochemical Features

All neurons are not created equal. Certain cell populations in specific brain regions are more susceptible to age-related changes that initiate regional and system-level dysfunction. In this respect, neurons in layer II of the entorhinal cortex are selectively vulnerable in aging and Alzheimer's disease (AD). This paper will cover several hypotheses that attempt to account for age-related alterations among this cell population. We consider whether specific developmental, anatomical, or biochemical features of neurons in layer II of the entorhinal cortex contribute to their particular sensitivity to aging and AD. The entorhinal cortex is a functionally heterogeneous environment, and we will also review data suggesting that, within the entorhinal cortex, there is subregional specificity for molecular alterations that may initiate cognitive decline. Taken together, the existing data point to a regional cascade in which entorhinal cortical alterations directly contribute to downstream changes in its primary afferent region, the hippocampus.

scholarly journals Communicability Characterization of Structural DWI Subcortical Networks in Alzheimer’s Disease

Entropy ◽  
2019 ◽  
Vol 21 (5) ◽  
pp. 475 ◽  
Author(s):  
Eufemia Lella ◽  
Nicola Amoroso ◽  
Domenico Diacono ◽  
Angela Lombardi ◽  
Tommaso Maggipinto ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Brain Network ◽  
Data Set ◽  
Brain Connectome ◽  
Subcortical Brain ◽  
Classification Framework ◽  
Subcortical Regions ◽  
Cortical Regions

In this paper, we investigate the connectivity alterations of the subcortical brain network due to Alzheimer’s disease (AD). Mostly, the literature investigated AD connectivity abnormalities at the whole brain level or at the cortex level, while very few studies focused on the sub-network composed only by the subcortical regions, especially using diffusion-weighted imaging (DWI) data. In this work, we examine a mixed cohort including 46 healthy controls (HC) and 40 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data set. We reconstruct the brain connectome through the use of state of the art tractography algorithms and we propose a method based on graph communicability to enhance the information content of subcortical brain regions in discriminating AD. We develop a classification framework, achieving 77% of area under the receiver operating characteristic (ROC) curve in the binary discrimination AD vs. HC only using a 12 × 12 subcortical features matrix. We find some interesting AD-related connectivity patterns highlighting that subcortical regions tend to increase their communicability through cortical regions to compensate the physical connectivity reduction between them due to AD. This study also suggests that AD connectivity alterations mostly regard the inter-connectivity between subcortical and cortical regions rather than the intra-subcortical connectivity.

scholarly journals A Meta-Analysis of Brain DNA Methylation Across Sex, Age, and Alzheimer's Disease Points for Accelerated Epigenetic Aging in Neurodegeneration

2021 ◽  
Vol 13 ◽  
Author(s):  
Camilla Pellegrini ◽  
Chiara Pirazzini ◽  
Claudia Sala ◽  
Luisa Sambati ◽  
Igor Yusipov ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Healthy Adult ◽  
Meta Analysis ◽  
Brain Regions ◽  
Epigenetic Aging ◽  
High Concordance ◽  
Males And Females ◽  
Cortical Regions

Alzheimer's disease (AD) is characterized by specific alterations of brain DNA methylation (DNAm) patterns. Age and sex, two major risk factors for AD, are also known to largely affect the epigenetic profiles in brain, but their contribution to AD-associated DNAm changes has been poorly investigated. In this study we considered publicly available DNAm datasets of four brain regions (temporal, frontal, entorhinal cortex, and cerebellum) from healthy adult subjects and AD patients, and performed a meta-analysis to identify sex-, age-, and AD-associated epigenetic profiles. In one of these datasets it was also possible to distinguish 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) profiles. We showed that DNAm differences between males and females tend to be shared between the four brain regions, while aging differently affects cortical regions compared to cerebellum. We found that the proportion of sex-dependent probes whose methylation is modified also during aging is higher than expected, but that differences between males and females tend to be maintained, with only a few probes showing age-by-sex interaction. We did not find significant overlaps between AD- and sex-associated probes, nor disease-by-sex interaction effects. On the contrary, we found that AD-related epigenetic modifications are significantly enriched in probes whose DNAm varies with age and that there is a high concordance between the direction of changes (hyper or hypo-methylation) in aging and AD, supporting accelerated epigenetic aging in the disease. In summary, our results suggest that age-associated DNAm patterns concur to the epigenetic deregulation observed in AD, providing new insights on how advanced age enables neurodegeneration.

Sign in / Sign up

Export Citation Format

Share Document