Sex Differences in Behavior and Molecular Pathology in the 5XFAD Model

2021 ◽  
pp. 1-24
Author(s):  
Annesha Sil ◽  
Arina Erfani ◽  
Nicola Lamb ◽  
Rachel Copland ◽  
Gernot Riedel ◽  
...  
Keyword(s):  
Molecular Pathology ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Amyloid Β ◽  
Wild Type Littermate ◽  
Protective Mechanisms ◽  
Stress Markers ◽  
Behavioral Paradigm ◽  
5Xfad Mice ◽  
The Impact

Background: The prevalence of Alzheimer’s disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD. Objective: Here, we studied behavior and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, versus their wild-type littermate controls, to compared both sex- and genotype-dependent differences. Methods: A novel behavioral paradigm was utilized (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and western blotting. Results: Female 5XFAD mice had higher levels of human APP and amyloid-β and heightened inflammation versus males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance. Conclusion: The impact of sex on AD-relevant phenotypes is in line with human data and emphasizes the necessity of appropriate study design and reporting. Differential molecular profiles observed in male versus female mice offer insights into possible protective mechanisms, and hence treatment strategies.

scholarly journals Sex differences in behaviour and molecular pathology in the 5XFAD model

2021 ◽  
Author(s):  
Annesha Sil ◽  
Arina Erfani ◽  
Nicola Lamb ◽  
Rachel Copland ◽  
Gernot Riedel ◽  
...  
Keyword(s):  
Molecular Pathology ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Wild Type Littermate ◽  
Protective Mechanisms ◽  
Stress Markers ◽  
Amyloid Load ◽  
Activity Measures ◽  
5Xfad Mice ◽  
The Impact

ABSTRACTBackgroundThe prevalence of Alzheimer’s Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.ObjectiveHere, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, vs. their wild-type littermate controls, to compared both sex- and genotype-dependent differences.MethodsA novel behavioural paradigm was utilised (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and Western blotting.ResultsFemale 5XFAD mice had higher levels of human APP and beta-amyloid (Aβ) and heightened inflammation vs males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with cognitive performance.ConclusionThe impact of sex on AD-relevant phenotypes is in line with human data and emphasises the necessity of appropriate study design and reporting. Differential molecular profiles observed in male vs. female mice offer insights into possible protective mechanisms, and hence treatment strategies.

scholarly journals Amyloid β oligomer selective antibodies for Alzheimers therapeutics and diagnostics

2021 ◽  
Author(s):  
Kirsten L Viola ◽  
Maira A Bicca ◽  
Adrian M Bebenek ◽  
Daniel L Kranz ◽  
Vikas Nandwana ◽  
...  
Keyword(s):  
Memory Loss ◽  
Amyloid Β ◽  
Intraventricular Injection ◽  
Post Inoculation ◽  
Wild Type ◽  
Memory Dysfunction ◽  
Imaging Methods ◽  
5Xfad Mice ◽  
The Impact

Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques- species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce a promising anti-AβO diagnostic probe capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 hours. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.

scholarly journals 316 - Lewy Body Study: An Australian longitudinal biomarker study of dementia with Lewy bodies

2020 ◽  
Vol 32 (S1) ◽  
pp. 74-74
Author(s):  
Kai Sin Chin ◽  
Nawaf Yassi ◽  
Zina Hijazi ◽  
Victor Villemagne ◽  
Christopher Rowe ◽  
...  
Keyword(s):  
Dementia With Lewy Bodies ◽  
Clinical Symptoms ◽  
Treatment Strategies ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Tissue Donation ◽  
Cognitive Assessments ◽  
People With Dementia ◽  
Longitudinal Biomarker ◽  
The Impact

Background:Cerebral multi-morbidity is common in older people with dementia, including people with dementia with Lewy bodies (DLB). We describe the first Australian-based, longitudinal observational biomarker study of DLB.Aims:To investigate the frequency and influence of Alzheimer’s disease (AD) pathology (amyloid-β and tau) and cerebrovascular disease on clinical symptoms and disease outcome in DLB.Methods:The study will recruit 100 people with mild to moderate probable DLB, who will undergo comprehensive clinical and cognitive assessments. Scales targeting DLB-specific clinical features (such as cognitive fluctuations and rapid eye movement sleep behaviour disorder) are administered. Biomarker protocols incorporate blood sampling (including ApoE genotyping and systemic inflammatory markers), molecular imaging (amyloid-β [18F-NAV 4694], tau [18F-MK6240], VMAT2 [18F-AV133] PET scans), 3-tesla magnetic resonance imaging and optional lumbar puncture. Clinical assessments are completed 6 - monthly and imaging 18-monthly. Participants are also invited to register for post-mortem brain tissue donation.Results:Thirty participants with probable DLB have been enrolled to date (mean age 75.4 years, range 64-82; 87% male). All participants have mild to moderate cognitive impairment (mean MMSE 25, range 17-30). Approximately 64% of the participants were amyloid-β positive. Study procedure tolerability has been excellent with no adverse events reported.Conclusions:There is significant overlap of AD-related proteinopathies in people with DLB. Understanding the impact of multi-morbidity is essential in the development of effective treatment strategies. This study supports the feasibility of intensive, longitudinal biomarker studies in DLB in the Australian setting.

Traumatic Injury Reduces Amyloid Plaque Burden in the Transgenic 5xFAD Alzheimer’s Mouse Spinal Cord

2020 ◽  
Vol 77 (3) ◽  
pp. 1315-1330
Author(s):  
Tak-Ho Chu ◽  
Karen Cummins ◽  
Peter K. Stys
Keyword(s):  
Spinal Cord ◽  
Axonal Injury ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Deposition ◽  
Plaque Burden ◽  
Wild Type ◽  
Plaque Deposition ◽  
5Xfad Mice ◽  
The Impact

Background: Axonal injury has been implicated in the development of amyloid-β in experimental brain injuries and clinical cases. The anatomy of the spinal cord provides a tractable model for examining the effects of trauma on amyloid deposition. Objective: Our goal was to examine the effects of axonal injury on plaque formation and clearance using wild type and 5xFAD transgenic Alzheimer’s disease mice. Methods: We contused the spinal cord at the T12 spinal level at 10 weeks, an age at which no amyloid plaques spontaneously accumulate in 5xFAD mice. We then explored plaque clearance by impacting spinal cords in 27-week-old 5xFAD mice where amyloid deposition is already well established. We also examined the cellular expression of one of the most prominent amyloid-β degradation enzymes, neprilysin, at the lesion site. Results: No plaques were found in wild type animals at any time points examined. Injury in 5xFAD prevented plaque deposition rostral and caudal to the lesion when the cords were examined at 2 and 4 months after the impact, whereas age-matched naïve 5xFAD mice showed extensive amyloid plaque deposition. A massive reduction in the number of plaques around the lesion was found as early as 7 days after the impact, preceded by neprilysin upregulation in astrocytes at 3 days after injury. At 7 days after injury, the majority of amyloid was found inside microglia/macrophages. Conclusion: These observations suggest that the efficient amyloid clearance after injury in the cord may be driven by the orchestrated efforts of astroglial and immune cells.

scholarly journals Inhibitory Neural Network’s Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 698
Author(s):  
Hyeon Jeong Seo ◽  
Jung Eun Park ◽  
Seong-Min Choi ◽  
Taekyoung Kim ◽  
Soo Hyun Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Signal Transmission ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.

scholarly journals The role of sensory and olfactory pathways in multiple chemical sensitivity

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Beniamino Palmieri ◽  
Veronica Corazzari ◽  
Maria Vadalaʹ ◽  
Annamaria Vallelunga ◽  
Julio César Morales-Medina ◽  
...  
Keyword(s):  
Olfactory System ◽  
Clinical Symptoms ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Multiple Chemical Sensitivity ◽  
Chemical Sensitivity ◽  
Economic Implications ◽  
Chemical Intolerance ◽  
The Impact ◽  
Multiple Chemical

AbstractMultiple chemical sensitivity (MCS) is characterised by non-specific and recurring symptoms affecting multiple organs and associated with exposure to chemicals, even at low concentrations, which are, under normal circumstances, harmless to the general population. Symptoms include general discomfort, cardiovascular instability, irritation of the sensory organs, breath disorders, hypersensitivity affecting the skin and epithelial lining of the gut, throat and lungs, anxiety, and learning and memory loss. Chemical intolerance is a key distinguishing feature of MCS, limiting considerably patients’ lifestyle with serious social, occupational and economic implications. Since no specific diagnostic markers are currently available for chemical intolerance, the diagnosis relies on clinical symptoms. Despite the formulation of several hypotheses regarding the pathophysiology of MCS, its mechanisms remain undefined. A person-centred care approach, based on multidisciplinary and individualised medical plans, has shown promising results. However, more definite treatment strategies are required. We have reviewed the main experimental studies on MCS pathophysiology, focusing on the brain networks involved, the impact of environmental pollution on the olfactory system and the correlation with other pathologies such as neurodegenerative diseases. Finally, we discuss treatment strategies targeting the olfactory system.

scholarly journals Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease

2021 ◽  
Vol 118 (3) ◽  
pp. e2017742118
Author(s):  
Daniel C. Ellwanger ◽  
Shoutang Wang ◽  
Simone Brioschi ◽  
Zhifei Shao ◽  
Lydia Green ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Expression Patterns ◽  
Amyloid Β ◽  
Microglia Activation ◽  
Repeated Treatment ◽  
Systemic Injection ◽  
Mhc Ii ◽  
5Xfad Mice ◽  
The Impact

Triggering receptor expressed on myeloid cells 2 (TREM2) sustains microglia response to brain injury stimuli including apoptotic cells, myelin damage, and amyloid β (Aβ). Alzheimer’s disease (AD) risk is associated with the TREM2R47H variant, which impairs ligand binding and consequently microglia responses to Aβ pathology. Here, we show that TREM2 engagement by the mAb hT2AB as surrogate ligand activates microglia in 5XFAD transgenic mice that accumulate Aβ and express either the common TREM2 variant (TREM2CV) or TREM2R47H. scRNA-seq of microglia from TREM2CV-5XFAD mice treated once with control hIgG1 exposed four distinct trajectories of microglia activation leading to disease-associated (DAM), interferon-responsive (IFN-R), cycling (Cyc-M), and MHC-II expressing (MHC-II) microglia types. All of these were underrepresented in TREM2R47H-5XFAD mice, suggesting that TREM2 ligand engagement is required for microglia activation trajectories. Moreover, Cyc-M and IFN-R microglia were more abundant in female than male TREM2CV-5XFAD mice, likely due to greater Aβ load in female 5XFAD mice. A single systemic injection of hT2AB replenished Cyc-M, IFN-R, and MHC-II pools in TREM2R47H-5XFAD mice. In TREM2CV-5XFAD mice, however, hT2AB brought the representation of male Cyc-M and IFN-R microglia closer to that of females, in which these trajectories had already reached maximum capacity. Moreover, hT2AB induced shifts in gene expression patterns in all microglial pools without affecting representation. Repeated treatment with a murinized hT2AB version over 10 d increased chemokines brain content in TREM2R47H-5XFAD mice, consistent with microglia expansion. Thus, the impact of hT2AB on microglia is shaped by the extent of TREM2 endogenous ligand engagement and basal microglia activation.

scholarly journals TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

2016 ◽  
Vol 213 (5) ◽  
pp. 667-675 ◽  
Author(s):  
Yaming Wang ◽  
Tyler K. Ulland ◽  
Jason D. Ulrich ◽  
Wilbur Song ◽  
John A. Tzaferis ◽  
...  
Keyword(s):  
Neuronal Degeneration ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Early Time ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Increased Risk ◽  
5Xfad Mice ◽  
Microglial Response ◽  
The Impact

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.

Воздействиеультразвуковогополянадинамическуювязкостьводы

2019 ◽  
pp. 27-29
Author(s):  
P. Vikulin ◽  
K. Khlopov ◽  
M. Cherkashin
Keyword(s):  
Dynamic Viscosity ◽  
Experimental Studies ◽  
Ultrasonic Field ◽  
Maximum Effect ◽  
Ultrasonic Frequency ◽  
Ultrasonic Vibrations ◽  
Wastewater Disposal ◽  
Laboratory Setup ◽  
Sonic Treatment ◽  
The Impact

Enhancing water purification processes is provided by various methods including physical ones, in particular, exposure to ultrasonic vibrations. The change in the dynamic viscosity of water affects the rate of deposition of particles in the aquatic environment which can be used in natural and wastewater treatment. At the Department Water Supply and Wastewater Disposal of the National Research Moscow State University of Civil Engineering experimental studies were conducted under laboratory conditions to study the effect of ultrasound on the change in the dynamic viscosity of water. A laboratory setup has been designed consisting of an ultrasonic frequency generator of the relative intensity, a transducer (concentrator) that transmits ultrasonic vibrations to the source water, and sonic treatment tanks. Experimental studies on the impact of the ultrasonic field in the cavitation mode on the dynamic viscosity of the aqueous medium were carried out the exposure time was obtained to achieve the maximum effect.Интенсификация процессов очистки воды осуществляется с помощью различных методов, в том числе и физических, в частности воздействием ультразвуковых колебаний. Изменение динамической вязкости воды влияет на скорость осаждения частиц в водной среде, что может быть использовано в процессах очистки природных и сточных вод. На кафедре Водоснабжение и водоотведение Национального исследовательского Московского государственного строительного университета в лабораторных условиях проведены экспериментальные исследования по изучению влияния ультразвука на изменение динамической вязкости воды. Разработана схема лабораторной установки, состоящая из генератора ультразвуковых частот с соответствующей интенсивностью, преобразователя (концентратора), передающего ультразвуковые колебания в исходную воду, и емкости для озвучивания. Выполнены экспериментальные исследования по влиянию ультразвукового поля в режиме кавитации на динамическую вязкость водной среды, получено время экспозиции для достижения максимального эффекта.

Prediction of Disease Comorbidity Using HeteSim Scores based on Multiple Heterogeneous Networks

2019 ◽  
Vol 19 (4) ◽  
pp. 232-241 ◽  
Author(s):  
Xuegong Chen ◽  
Wanwan Shi ◽  
Lei Deng
Keyword(s):  
Protein Interactions ◽  
Experimental Studies ◽  
Treatment Strategies ◽  
Computational Method ◽  
Biological Information ◽  
Support Vector ◽  
Protein Protein Interactions ◽  
Efficient Treatment ◽  
Disease Associations ◽  
Previous State

Background: Accumulating experimental studies have indicated that disease comorbidity causes additional pain to patients and leads to the failure of standard treatments compared to patients who have a single disease. Therefore, accurate prediction of potential comorbidity is essential to design more efficient treatment strategies. However, only a few disease comorbidities have been discovered in the clinic. Objective: In this work, we propose PCHS, an effective computational method for predicting disease comorbidity. Materials and Methods: We utilized the HeteSim measure to calculate the relatedness score for different disease pairs in the global heterogeneous network, which integrates six networks based on biological information, including disease-disease associations, drug-drug interactions, protein-protein interactions and associations among them. We built the prediction model using the Support Vector Machine (SVM) based on the HeteSim scores. Results and Conclusion: The results showed that PCHS performed significantly better than previous state-of-the-art approaches and achieved an AUC score of 0.90 in 10-fold cross-validation. Furthermore, some of our predictions have been verified in literatures, indicating the effectiveness of our method.

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