scholarly journals 3D mapping reveals network-specific amyloid progression and subcortical susceptibility in mice

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Rebecca Gail Canter ◽  
Wen-Chin Huang ◽  
Heejin Choi ◽  
Jun Wang ◽  
Lauren Ashley Watson ◽  
...  
Keyword(s):  
Memory Loss ◽  
Brain Regions ◽  
Mammillary Body ◽  
Memory Circuit ◽  
Neurodegenerative Dementia ◽  
5Xfad Mouse ◽  
Intact Brain ◽  
Biological Discovery ◽  
Amyloid Aβ ◽  
Processing Techniques

Abstract Alzheimer’s disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD.

scholarly journals 3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility

2017 ◽  
Author(s):  
RG Canter ◽  
H Choi ◽  
J Wang ◽  
LA Watson ◽  
CG Yao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Mouse Model ◽  
Complex Networks ◽  
Memory Loss ◽  
Beta Amyloid ◽  
3D Mapping ◽  
Mammillary Body ◽  
Aβ Peptides ◽  
Amyloid Aβ ◽  
Memory Structures

AbstractAlzheimer’s disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (Aβ) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of Aβ deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to Aβ accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early Aβ aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt Aβ burden. Finally, we confirm Aβ in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to Aβ deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.Author ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.RGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.HC built the custom microscope.RGC, L-HT, KC, ID wrote the manuscript.

scholarly journals ADeditome provides the genomic landscape of A-to-I RNA editing in Alzheimer’s disease

2021 ◽  
Author(s):  
Sijia Wu ◽  
Mengyuan Yang ◽  
Pora Kim ◽  
Xiaobo Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rna Editing ◽  
Memory Loss ◽  
Brain Regions ◽  
Disease Stage ◽  
Mirna Regulation ◽  
Annotation Database ◽  
Functional Annotations ◽  
Genomic Landscape

Abstract A-to-I RNA editing, contributing to nearly 90% of all editing events in human, has been reported to involve in the pathogenesis of Alzheimer’s disease (AD) due to its roles in brain development and immune regulation, such as the deficient editing of GluA2 Q/R related to cell death and memory loss. Currently, there are urgent needs for the systematic annotations of A-to-I RNA editing events in AD. Here, we built ADeditome, the annotation database of A-to-I RNA editing in AD available at https://ccsm.uth.edu/ADeditome, aiming to provide a resource and reference for functional annotation of A-to-I RNA editing in AD to identify therapeutically targetable genes in an individual. We detected 1676 363 editing sites in 1524 samples across nine brain regions from ROSMAP, MayoRNAseq and MSBB. For these editing events, we performed multiple functional annotations including identification of specific and disease stage associated editing events and the influence of editing events on gene expression, protein recoding, alternative splicing and miRNA regulation for all the genes, especially for AD-related genes in order to explore the pathology of AD. Combing all the analysis results, we found 108 010 and 26 168 editing events which may promote or inhibit AD progression, respectively. We also found 5582 brain region-specific editing events with potentially dual roles in AD across different brain regions. ADeditome will be a unique resource for AD and drug research communities to identify therapeutically targetable editing events. Significance: ADeditome is the first comprehensive resource of the functional genomics of individual A-to-I RNA editing events in AD, which will be useful for many researchers in the fields of AD pathology, precision medicine, and therapeutic researches.

RPPAware: A software suite to preprocess, analyze and visualize reverse phase protein array data

2018 ◽  
Vol 16 (03) ◽  
pp. 1850001 ◽  
Author(s):  
A. Ranjitha Dhanasekaran ◽  
Katheleen J. Gardiner
Keyword(s):  
Brain Regions ◽  
Large Datasets ◽  
Ease Of Use ◽  
Statistical Features ◽  
Software Suite ◽  
Reverse Phase ◽  
High Throughput Technology ◽  
Phase Protein ◽  
Biological Discovery

Reverse Phase Protein Arrays (RPPA) is a high-throughput technology used to profile levels of protein expression. Handling the large datasets generated by RPPA can be facilitated by appropriate software tools. Here, we describe RPPAware, a free and intuitive software suite that was developed specifically for analysis and visualization of RPPA data. RPPAware is a portable tool that requires no installation and was built using Java. Many modules of the tool invoke R to utilize the statistical features. To demonstrate the utility of RPPAware, data generated from screening brain regions of a mouse model of Down syndrome with 62 antibodies were used as a case study. The ease of use and efficiency of RPPAware can accelerate data analysis to facilitate biological discovery. RPPAware 1.0 is freely available under GNU General Public License from the project website at http://downsyndrome.ucdenver.edu/iddrc/rppaware/home.htm along with a full documentation of the tool.

scholarly journals Alterations of Expression of the Serotonin 5-HT4 Receptor in Brain Disorders

2018 ◽  
Vol 19 (11) ◽  
pp. 3581 ◽  
Author(s):  
Heike Rebholz ◽  
Eitan Friedman ◽  
Julia Castello
Keyword(s):  
Executive Function ◽  
Food Intake ◽  
Serotonin Receptor ◽  
Current Knowledge ◽  
Memory Loss ◽  
Brain Regions ◽  
Brain Disorders ◽  
Protein Levels ◽  
Preclinical Animal Models ◽  
Mood Depression

The serotonin 4 receptor, 5-HT4R, represents one of seven different serotonin receptor families and is implicated in a variety of physiological functions and their pathophysiological variants, such as mood and depression or anxiety, food intake and obesity or anorexia, or memory and memory loss in Alzheimer’s disease. Its central nervous system expression pattern in the forebrain, in particular in caudate putamen, the hippocampus and to lesser extent in the cortex, predispose it for a role in executive function and reward-related actions. In rodents, regional overexpression or knockdown in the prefrontal cortex or the nucleus accumbens of 5-HT4R was shown to impact mood and depression-like phenotypes, food intake and hypophagia; however, whether expression changes are causally involved in the etiology of such disorders is not clear. In this context, more data are emerging, especially based on PET technology and the use of ligand tracers that demonstrate altered 5-HT4R expression in brain disorders in humans, confirming data stemming from post-mortem tissue and preclinical animal models. In this review, we would like to present the current knowledge of 5-HT4R expression in brain regions relevant to mood/depression, reward and executive function with a focus on 5-HT4R expression changes in brain disorders or caused by drug treatment, at both the transcript and protein levels.

scholarly journals Noncanonical function of an autophagy protein prevents spontaneous Alzheimer’s disease

2020 ◽  
Vol 6 (33) ◽  
pp. eabb9036
Author(s):  
Bradlee L. Heckmann ◽  
Brett J. W. Teubner ◽  
Emilio Boada-Romero ◽  
Bart Tummers ◽  
Clifford Guy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Disease ◽  
Memory Impairment ◽  
Memory Loss ◽  
Tau Hyperphosphorylation ◽  
Primary Microglia ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Noncanonical functions of autophagy proteins have been implicated in neurodegenerative conditions, including Alzheimer’s disease (AD). The WD domain of the autophagy protein Atg16L is dispensable for canonical autophagy but required for its noncanonical functions. Two-year-old mice lacking this domain presented with robust β-amyloid (Aβ) pathology, tau hyperphosphorylation, reactive microgliosis, pervasive neurodegeneration, and severe behavioral and memory deficiencies, consistent with human disease. Mechanistically, we found this WD domain was required for the recycling of Aβ receptors in primary microglia. Pharmacologic suppression of neuroinflammation reversed established memory impairment and markers of disease pathology in this novel AD model. Therefore, loss of the Atg16L WD domain drives spontaneous AD in mice, and inhibition of neuroinflammation is a potential therapeutic approach for treating neurodegeneration and memory loss. A decline in expression of ATG16L in the brains of human patients with AD suggests the possibility that a similar mechanism may contribute in human disease.

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models

2019 ◽  
Author(s):  
Isabel Castanho ◽  
Tracey K. Murray ◽  
Eilis Hannon ◽  
Aaron Jeffries ◽  
Emma Walker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Entorhinal Cortex ◽  
Rare Variants ◽  
Late Onset ◽  
Brain Regions ◽  
Response Component ◽  
Recent Success ◽  
Sequencing Studies ◽  
Transcriptional Changes ◽  
Amyloid Aβ

AbstractThe onset and progression of Alzheimer’s disease (AD) is characterized by increasing intracellular aggregation of hyperphosphorylated tau protein and accumulation of β-amyloid (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD the transcriptional mechanisms involved in disease progression are not fully understood. We used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the development of both tau and amyloid pathology. Using highly-parallel RNA sequencing we profiled transcriptional variation in the entorhinal cortex at four time points identifying robust genotype-associated differences in entorhinal cortex gene expression in both models. We quantified neuropathological burden across multiple brain regions in the same individual mice, identifying widespread changes in gene expression paralleling the development of tau pathology in rTg4510 mice. Differentially expressed transcripts included genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in GWAS and exome-sequencing studies of late-onset sporadic AD. Systems-level analyses identified discrete co-expression networks associated with the progressive accumulation of tau, with these enriched for genes and pathways previously implicated in the neuro-immunological and neurodegenerative processes driving AD pathology. Finally, we report considerable overlap between tau-associated networks and AD-associated co-expression modules identified in the human cortex. Our data provide further support for an immune-response component in the accumulation of tau, and reveal novel molecular pathways associated with the progression of AD neuropathology.

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 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 Alzheimer’s disease under the purview of Graph Theory Centric Genetic Networks

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yegnanarayanan Venkatraman ◽  
◽  
Narayanaa Y Krithicaa ◽  
Valentina E. Balas ◽  
Marius M. Balas ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Graph Theory ◽  
Network Theory ◽  
Memory Loss ◽  
Amyloid Plaque ◽  
Brain Regions ◽  
Protein Protein Interaction ◽  
Communication Demands ◽  
The Brain

Notice that the synapsis of brain is a form of communication. As communication demands connectivity, it is not a surprise that "graph theory" is a fastest growing area of research in the life sciences. It attempts to explain the connections and communication between networks of neurons. Alzheimer’s disease (AD) progression in brain is due to a deposition and development of amyloid plaque and the loss of communication between nerve cells. Graph/network theory can provide incredible insights into the incorrect wiring leading to memory loss in a progressive manner. Network in AD is slanted towards investigating the intricate patterns of interconnections found in the pathogenesis of brain. Here, we see how the notions of graph/network theory can be prudently exploited to comprehend the Alzheimer’s disease. We begin with introducing concepts of graph/network theory as a model for specific genetic hubs of the brain regions and cellular signalling. We begin with a brief introduction of prevalence and causes of AD followed by outlining its genetic and signalling pathogenesis. We then present some of the network-applied outcome in assessing the disease-signalling interactions, signal transduction of protein-protein interaction, disturbed genetics and signalling pathways as compelling targets of pathogenesis of the disease.

scholarly journals Stimulation of the posterior cingulate impairs episodic memory encoding

2018 ◽  
Author(s):  
Vaidehi S. Natu ◽  
Jui-Jui Lin ◽  
Alexis Burks ◽  
Akshay Arora ◽  
Michael D. Rugg ◽  
...  
Keyword(s):  
Episodic Memory ◽  
A Priori ◽  
Memory Loss ◽  
Brain Regions ◽  
Posterior Cingulate Cortex ◽  
Memory Encoding ◽  
Posterior Cingulate ◽  
Simultaneous Acquisition ◽  
Hippocampal Activity ◽  
Gamma Power

Neuroimaging experiments implicate the posterior cingulate cortex (PCC) in episodic memory processing, making it a potential target for responsive neuromodulation strategies outside of the hippocampal network. However, causal evidence for the role PCC plays in memory encoding is lacking. In patients undergoing seizure mapping, we investigated functional properties of the PCC using deep brain stimulation (DBS) and stereotactic electroencephalography (stereo EEG). These techniques allow precise targeting of deep cortical structures including the PCC, and simultaneous acquisition of oscillatory recordings from neighboring regions such as the hippocampus. We used a free recall experiment in which PCC was stimulated during item encoding period of half of the study lists, while no stimulation was applied during encoding period of the remaining lists. We evaluated if stimulation affected memory and/or modulated hippocampal activity. Results revealed four main findings. (i) Stimulation during encoding impaired memory for early items on the study lists. (ii) Stimulation increased hippocampal gamma band power. (iii) Stimulation-induced gamma power predicted memory impairment. (iv) Functional connectivity between the hippocampus and PCC predicted the degree of stimulation effect on memory. Our findings offer the first causal evidence implicating the PCC in episodic memory encoding. Importantly, results highlight that stimulation targeted outside of the temporal lobe can modulate hippocampal activity with implications on behavior. Furthermore, a-priori measures of connectivity between brain regions within a functional network can be informative in predicting behavioral effects of stimulation. Our findings have significant implications for developing therapies to treat diseases of memory loss and cognitive impairment using DBS.

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