scholarly journals NMR analysis of the correlation of metabolic changes in blood and cerebrospinal fluid in Alzheimer model male and female mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0250568
Author(s):  
Filip Stojanovic ◽  
Mariam Taktek ◽  
Nam Huan Khieu ◽  
Junzhou Huang ◽  
Susan Jiang ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Metabolic Profile ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Body Fluids ◽  
Metabolic Changes ◽  
Treatment And Prevention ◽  
Novel Method ◽  
Metabolism Analysis

The development of effective therapies as well as early, molecular diagnosis of Alzheimer’s disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer’s patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid β (Aβ) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP/PS1 mouse model can provide information about metabolic changes in these body fluids caused by Aβ accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.

scholarly journals NMR Analysis of the Correlation of Metabolic Changes in Blood and Cerebrospinal Fluid in Alzheimer Model Male and Female Mice

2020 ◽  
Author(s):  
Filip Stojanovic ◽  
Mariam Taktek ◽  
Nam Huan Khieu ◽  
Junzhou Huang ◽  
Susan Jiang ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Metabolic Profile ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Body Fluids ◽  
Metabolic Changes ◽  
Treatment And Prevention ◽  
Novel Method ◽  
Metabolism Analysis

AbstractThe development of effective therapies as well as early, molecular diagnosis of Alzheimer’s disease is impeded by the lack of understanding of the underlying pathological mechanisms. Metabolomics studies of body fluids as well as brain tissues have shown major changes in metabolic profiles of Alzheimer’s patients. However, with analysis performed at the late stages of the disease it is not possible to distinguish causes and consequence. The mouse model APP/PS1 expresses a mutant amyloid precursor protein resulting in early Amyloid β (Aβ) accumulation as well as many resulting physiological changes including changes in metabolic profile and metabolism. Analysis of metabolic profile of cerebrospinal fluid (CSF) and blood of APP/PS1 mouse model can provide information about metabolic changes in these body fluids caused by Aβ accumulation. Using our novel method for analysis of correlation and mathematical ranking of significant correlations between metabolites in CSF and blood, we have explored changes in metabolite correlation and connectedness in APP/PS1 and wild type mice. Metabolites concentration and correlation changes in CSF, blood and across the blood brain barrier determined in this work are affected by the production of amyloid plaque. Metabolite changes observed in the APP/PS1 mouse model are the response to the mutation causing plaque formation, not the cause for the plaque suggesting that they are less relevant in the context of early treatment and prevention then the metabolic changes observed only in humans.

scholarly journals Using intracerebral microdialysis to probe the efficacy of repurposed drugs in Alzheimer′s disease pathology

2022 ◽  
Author(s):  
Christiana Bjorkli ◽  
Mary Hemler ◽  
Joshua Julian ◽  
Axel Sandvig ◽  
Ioanna Sandvig
Keyword(s):  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Cognitive Decline ◽  
Memory Performance ◽  
Time Windows ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Intracerebral Microdialysis ◽  
Unexpected Finding ◽  
Repurposed Drugs

All disease-targeting drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer′s disease patients. Even the recently approved drug Aducanumab, has proven effective in removing amyloid-β, but does not reduce cognitive decline. This emphasizes the urgent need for novel therapeutic approaches that could reduce several AD neuropathologies simultaneously, eventually leading to improved cognitive performance. To validate whether our mouse model replicates AD neuropathology as observed in patients, we characterized the 3xTg AD mouse model to avoid premature translation of successful results. In this study we have repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting the Wnt signaling and endosomal-lysosomal pathway respectively, to test their potential to attenuate AD pathology. Using intracerebral microdialysis, we simultaneously infused these disease-targeting drugs between 1-2 weeks, separately and also in combination, while collecting cerebrospinal fluid. We found that Fasudil reduces intracellular amyloid-β in young, and amyloid plaques in old animals, and overall cerebrospinal fluid amyloid-β. Lonafarnib reduces tau neuropathology and cerebrospinal fluid tau biomarkers in young and old animals. Co-infusion of both drugs was more effective in reducing intracellular amyloid-β than either drug alone, and appeared to improve contextual memory performance. However, an unexpected finding was that Lonafarnib treatment increased amyloid plaque size, suggesting that activating the endosomal-lysosomal system may inadvertently increase amyloid-β pathology if administered too late in the AD continuum. Taken together, these findings lend support to the application of repurposed drugs to attenuate AD neuropathology at various therapeutic time windows.

In Vivo Microdialysis in Mice Captures Changes in Alzheimer’s Disease Cerebrospinal Fluid Biomarkers Consistent with Developing Pathology

2021 ◽  
pp. 1-14
Author(s):  
Christiana Bjorkli ◽  
Claire Louet ◽  
Trude Helen Flo ◽  
Mary Hemler ◽  
Axel Sandvig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Intracerebral Microdialysis ◽  
Preclinical Models ◽  
The Brain

Background: Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal CSF monitoring. Objective: An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods: Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results: We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion: Our approach can further advance AD and other neurodegenerative research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal and can additionally be used to administer pharmaceutical compounds and assess their efficacy (Bjorkli, unpublished data).

scholarly journals Unbiased Approach to Counteract Upward Drift in Cerebrospinal Fluid Amyloid-β 1–42 Analysis Results

2018 ◽  
Vol 64 (3) ◽  
pp. 576-585 ◽  
Author(s):  
Betty M Tijms ◽  
Eline A J Willemse ◽  
Marissa D Zwan ◽  
Sandra D Mulder ◽  
Pieter Jelle Visser ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Gaussian Mixture ◽  
Mixture Modeling ◽  
Memory Clinic ◽  
The Past ◽  
Gaussian Mixture Modeling ◽  
Time Dependencies ◽  
The Brain

AbstractBACKGROUNDLow cerebrospinal fluid (CSF) amyloid-β 1–42 (Aβ 1–42) concentrations indicate amyloid plaque accumulation in the brain, a pathological hallmark of Alzheimer disease (AD). Innotest assay values of Aβ 1–42 have gradually increased over the past 2 decades, which might lead to misclassification of AD when a single cutpoint for abnormality is used. We propose an unbiased approach to statistically correct for drift.METHODSWe determined year-specific cutpoints with Gaussian mixture modeling, based on the cross-section of bimodal distributions of Aβ 1–42 concentrations in 4397 memory clinic patients. This allowed us to realign year-specific cutpoints as an unbiased method to remove drift from the data. Sensitivity and specificity to detect AD dementia were compared between corrected and uncorrected values.RESULTSAβ 1–42 values increased 22 pg/mL annually, and this could not be explained by changes in cohort composition. Our approach removed time dependencies [β (SE) = 0.07 (0.59); P = 0.91]. Statistically correcting for drift improved the sensitivity to detect AD dementia to 0.90 (95% CI, 0.89–0.92) from at least 0.66 (95% CI, 0.64–0.69) based on uncorrected data. Specificity became lower (0.69; 95% CI, 0.67–0.70) vs at most 0.80 (95% CI, 0.79–0.82) for uncorrected data.CONCLUSIONSThis approach may also be useful to standardize Aβ 1–42 CSF concentrations across different centers and/or platforms, and to optimize use of CSF biomarker data collected over a long period.

scholarly journals Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics

2018 ◽  
Vol 83 (1) ◽  
pp. 197-204 ◽  
Author(s):  
Brendan P. Lucey ◽  
Terry J. Hicks ◽  
Jennifer S. McLeland ◽  
Cristina D. Toedebusch ◽  
Jill Boyd ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Amyloid Β

scholarly journals Bacterial sepsis increases hippocampal fibrillar amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease

2021 ◽  
Vol 152 ◽  
pp. 105292
Author(s):  
Jacob M. Basak ◽  
Aura Ferreiro ◽  
Lucy S. Cohen ◽  
Patrick W. Sheehan ◽  
Collin J. Nadarajah ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Plaque ◽  
Bacterial Sepsis ◽  
Model Of Alzheimer’S Disease ◽  
Plaque Load

scholarly journals Comparison of metabolic changes after neoadjuvant endocrine and chemotherapy in ER-positive, HER2-negative breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ho Hyun Ryu ◽  
Sei Hyun Ahn ◽  
Seon Ok Kim ◽  
Jeong Eun Kim ◽  
Ji sun Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metabolic Profile ◽  
Fasting Glucose ◽  
Medical Center ◽  
Mean Value ◽  
Metabolic Changes ◽  
Phase Iii ◽  
Breast Cancer Patients ◽  
Neoadjuvant Endocrine Therapy ◽  
The Mean

AbstractSurvival of breast cancer patients has improved, and treatment-related changes regarding metabolic profile deterioration after neoadjuvant systemic treatment (NST) become important issues in cancer survivors. We sought to compare metabolic profile changes and the neutrophil-to-lymphocyte ratio (NLR) between patients undergoing neoadjuvant chemotherapy (NCT) and neoadjuvant endocrine therapy (NET) 3 years after the treatment. In a prospective, randomized, phase III trial which compared 24 weeks of NCT with adriamycin and cyclophosphamide followed by docetaxel and NET with goserelin and tamoxifen (NEST), 123 patients in the Asan Medical Center were retrospectively reviewed to evaluate metabolic changes, such as body mass index (BMI), blood pressure (BP), total cholesterol (TC), fasting glucose, and the NLR. The mean age of patients was 42 years. The changes in BMI, serum glucose, and TC during NST and after 3 years were significantly different between NCT and NET. The proportion of overweight + obese group and the mean BMI were significantly increased during NCT (26.6% to 37.5%, 22.84 kg/m2 to 23.87 kg/m2, p < 0.05), and these attributes found to have normalized at the 3-year follow-up. In the NET group, BMI changes were not observed (p > 0.05, all). There were no differences in changes over time among in the Hypertension group during NCT and NET (p = 0.96). The mean value of serum TC and fasting glucose significantly increased (< 0.05, both) during NCT and decreased 3 years after NCT (p < 0.05); however, no significant changes were observed in the NET group. The NLR was increased from 1.83 to 3.18 after NCT (p < 0.05) and decreased from 1.98 to 1.43 (p < 0.05) after NET. Compared with minimal metabolic effect of NET, NCT worsens metabolic profiles, which were recovered over 3 years. The NLR was increased after NCT but decreased after NET.

scholarly journals Blood-Brain Barrier Disruption Increases Amyloid-Related Pathology in TgSwDI Mice

2021 ◽  
Vol 22 (3) ◽  
pp. 1231
Author(s):  
Ihab M. Abdallah ◽  
Kamal M. Al-Shami ◽  
Euitaek Yang ◽  
Amal Kaddoumi
Keyword(s):  
Mouse Model ◽  
Blood Brain Barrier ◽  
High Throughput Screening ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Amyloid Angiopathy ◽  
Cancer Resistance ◽  
Screening Assay ◽  
Blood Brain ◽  
High Throughput Screening Assay

In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.

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