scholarly journals Reporting amyloid beta levels via bioluminescence imaging with amyloid reservoirs in Alzheimer's disease models

2021 ◽  
Author(s):  
Jing Yang ◽  
Weihua Ding ◽  
Biyue Zhu ◽  
Sherri Zhen ◽  
Shi Kuang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Bioluminescence Imaging ◽  
Daily Practice ◽  
Control Group ◽  
Preclinical Research ◽  
Bioluminescence Intensity ◽  
Time Points

Bioluminescence imaging has changed daily practice in preclinical research of cancers and other diseases in the last decades; however, it has been rarely applied in preclinical research of Alzheimer's disease (AD). In this report, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Abeta). Bioluminescence imaging has changed daily practice in preclinical research of cancers and other diseases in the last decades; however, it has been rarely applied in preclinical research of Alzheimer's disease (AD). In this report, we demonstrated that bioluminescence imaging could be used to report the levels of amyloid beta (Abeta) species in vivo. We hypothesized that AkaLumine, a newly discovered substrate for luciferase, could bind to Abeta aggregates and plaques. We further speculated that the Abeta species have the reservoir capacity to sequester and release AkaLumine to control the bioluminescence intensity, which could be used to report the levels of Abetas. Our hypotheses have been validated via in vitro solution tests, mimic studies with brain tissues and mice, two-photon imaging with AD mice, and in vivo bioluminescence imaging using transgenic AD mice that were virally transduced with aka Luciferase (AkaLuc), a new luciferase that generates bioluminescence in the near infrared window. As expected, compared to the control group, we observed that the Abeta group showed lower bioluminescence intensity due to AkaLumine sequestering at early time points, while higher intensity due to AkaLumine releasing at later time points. Lastly, we demonstrated that this method could be used to monitor AD progression and therapeutic effectiveness of avagacestat, a well-studied gamma-secretase inhibitor. Importantly, a good correlation (R2 = 0.81) was established between in vivo bioluminescence signals and Abeta burdens of the tested AD mice. We believe that our approach can be easily implemented into daily imaging experiments and has tremendous potential to change daily practice of preclinical AD research.

[18F]-florbetaben PET/CT Imaging in the Alzheimer’s Disease Mouse Model APPswe/PS1dE9

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
Author(s):  
J. Stenzel ◽  
C. Rühlmann ◽  
T. Lindner ◽  
S. Polei ◽  
S. Teipel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
New Drugs ◽  
Imaging Data ◽  
Wild Type ◽  
Preclinical Research ◽  
Standardized Uptake Values ◽  
Pet Ct

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [<sup>18</sup>F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [<sup>18</sup>F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [<sup>18</sup>F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [<sup>18</sup>F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [<sup>18</sup>F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.

Is Olfactory Epithelium Biopsy Useful for Confirming Alzheimer’s Disease?

2018 ◽  
Vol 128 (3) ◽  
pp. 184-192 ◽  
Author(s):  
Maria Dantas Costa Lima Godoy ◽  
Marco Aurélio Fornazieri ◽  
Richard L. Doty ◽  
Fábio de Rezende Pinna ◽  
José Marcelo Farfel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Olfactory Epithelium ◽  
Clinical Symptoms ◽  
Middle Turbinate ◽  
Superior Turbinate ◽  
Significant Difference ◽  
Amyloid Beta Proteins

Objectives: The clinical symptoms of Alzheimer’s disease (AD) are preceded by a long asymptomatic period associated with “silent” deposition of aberrant paired helical filament (PHF)-tau and amyloid-beta proteins in brain tissue. Similar depositions have been reported within the olfactory epithelium (OE), a tissue that can be biopsied in vivo. The degree to which such biopsies are useful in identifying AD is controversial. This postmortem study had 3 main goals: first, to quantify the relative densities of AD-related proteins in 3 regions of the olfactory neuroepithelium, namely, the nasal septum, middle turbinate, and superior turbinate; second, to establish whether such densities are correlated among these epithelial regions as well as with semi-quantitative ratings of general brain cortex pathology; and third, to evaluate correlations between the protein densities and measures of antemortem cognitive function. Methods: Postmortem blocks of olfactory mucosa were obtained from 12 AD cadavers and 24 controls and subjected to amyloid-beta and PHF-tau immunohistochemistry. Results: We observed marked heterogeneity in the presence of the biomarkers of tau and amyloid-beta among the targeted olfactory epithelial regions. No significant difference was observed between the cadavers with AD and the controls regarding the concentration of these proteins in any of these epithelial regions. Only one correlation significant was evident, namely, that between the tau protein densities of the middle and the upper turbinate ( r = .58, P = .002). Conclusion: AD-related biomarker heterogeneity, which has not been previously demonstrated, makes comparisons across studies difficult and throws into question the usefulness of OE amyloid-beta and PHF-tau biopsies in detecting AD.

scholarly journals Transcranial in vivo detection of amyloid-beta at single plaque resolution with large-field multifocal illumination fluorescence microscopy

2020 ◽  
Author(s):  
Ruiqing Ni ◽  
Zhenyue Chen ◽  
Gloria Shi ◽  
Alessia Villois ◽  
Quanyu Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescence Microscopy ◽  
Amyloid Beta ◽  
Large Field ◽  
Microscopy Technique ◽  
In Vivo Detection ◽  
Amyloid Deposits ◽  
Microscopy Techniques

AbstractThe abnormal deposition of beta-amyloid proteins in the brain is one of the major histopathological hallmarks of Alzheimer’s disease. Currently available intravital microscopy techniques for high-resolution plaque visualization commonly involve highly invasive procedures and are limited to a small field-of-view within the rodent brain. Here, we report the transcranial detection of amyloid-beta deposits at the whole brain scale with 20 μm resolution in APP/PS1 and arcAβ mouse models of Alzheimer’s disease amyloidosis using a large-field multifocal (LMI) fluorescence microscopy technique. Highly sensitive and specific detection of amyloid-beta deposits at a single plaque level in APP/PS1 and arcAβ mice was facilitated using luminescent conjugated oligothiophene HS-169. Immunohistochemical staining with HS-169, anti-Aβ antibody 6E10, and conformation antibodies OC (fibrillar) of brain tissue sections further showed that HS-169 resolved compact parenchymal and vessel-associated amyloid deposits. The novel imaging platform offers new prospects for in vivo studies into Alzheimer’s disease mechanisms in animal models as well as longitudinal monitoring of therapeutic responses at a single plaque level.

scholarly journals Evaluation of Plant Phenolic Metabolites as a Source of Alzheimer's Drug Leads

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Yara Hassaan ◽  
Heba Handoussa ◽  
Ahmed H. El-Khatib ◽  
Michael W. Linscheid ◽  
Nesrine El Sayed ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Epidemiological Studies ◽  
Aqueous Alcohol ◽  
Alcohol Extract ◽  
Y Maze ◽  
Pharmacological Screening

Epidemiological studies have proven an association between consumption of polyphenols and prevention of Alzheimer’s disease, the most common form of dementia characterized by extracellular deposition of amyloid beta plaques. The aim of this study is pharmacological screening of the aqueous alcohol extract ofMarkhamia platycalyxleaves,Schotia brachypetalaleaves and stalks, and piceatannol compared to aqueous alcohol extract ofCamellia sinensisleaves as potential Alzheimer’s disease drugs. LC-HRESI(-ve)-MSnwas performed to identify phenolics’ profile ofSchotia brachypetalastalks aqueous alcohol extract and revealed ten phenolic compounds as first report: daidzein, naringin, procyanidin isomers, procyanidin dimer gallate, quercetin 3-O-rhamnoside, quercetin 3-O-glucuronide, quercetin hexose gallic acid, quercetin hexose protocatechuic acid, and ellagic acid. Alzheimer’s disease was induced by a single intraperitoneal injection of LPS. Adult male Swiss albino mice were divided into groups of 8–10 mice each receiving treatment for six days.In vivobehavioral tests (Y maze and object recognition) andin vitroestimation of amyloid beta 42 by ELISA showed significant differences between results of treated and nontreated animals.

scholarly journals SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1275
Author(s):  
Soo Yong Park ◽  
Joo Yeong Kang ◽  
Taehee Lee ◽  
Donggyu Nam ◽  
Chang-Jin Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Physiological Activity ◽  
Precursor Protein ◽  
Age Related

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

scholarly journals Developing in vivo assays for investigation of p75NTR and NRH1 transmembrane domain cleavage events using zebrafish embryos

2020 ◽  
Author(s):  
Tanya Jayne ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Xenopus Laevis ◽  
Amyloid Beta ◽  
Transmembrane Domain ◽  
Chimeric Protein ◽  
Proteolytic Processing ◽  
Structural Basis ◽  
Secretase Inhibitor

Abstractγ-secretase is an important protease complex responsible for the cleavage of over 100 substrates within their transmembrane domains. γ-secretase acts in Alzheimer’s disease by cleavage of AMYLOID BETA (A4) PRECURSOR PROTEIN to produce aggregation-prone Amyloid beta peptide. Other γ-secretase substrates such as p75NTR are also relevant to Alzheimer’s disease. How γ-secretase cleavage site specificity is determined is still unclear. A previous study using Xenopus laevis to investigate the proteolytic processing of p75NTR and its homolog NRH1 found that transmembrane cleavage of NRH1 was not sensitive to the γ-secretase inhibitor DAPT, suggesting that it is not processed by γ-secretase. To investigate this further, we identified zebrafish orthologues of the genes p75NTR and NRH1 and developed in vivo assays to assess cleavage of the resultant p75NTR and Nrh1 proteins. Our observations from these assays in zebrafish are consistent with the Xenopus laevis study. Inhibition of γ-secretase by DAPT treatment results in accumulation of uncleaved p75NTR substrate, while cleavage of Nrh1 is not affected. This supports that p75NTR is cleaved by γ-secretase while Nrh1 is cleaved by a separate γ-secretase-like activity. We extended our approach by generating a chimeric Nrh1 protein in which the Nrh1 transmembrane domain was replaced by that of p75NTR, in an attempt to determine whether it is the p75NTR TMD that confers susceptibility for γ-secretase cleavage. Our results from analysis of this chimeric protein revealed that the p75NTR transmembrane domain alone is insufficient to confer γ-secretase cleavage susceptibility. This is not completely unexpected, as there is evidence to suggest that other factors are crucial for selection/cleavage by the γ-secretase complex. We have established a system in which we can now attempt to dissect the structural basis for γ-secretase cleavage specificity and evolution.

scholarly journals Modeling Aβ42 Accumulation in Response to Herpes Simplex Virus 1 Infection: 2D or 3D?

2020 ◽  
Author(s):  
Eric E. Abrahamson ◽  
Wenxiao Zheng ◽  
Vaishali Muralidaran ◽  
Milos D. Ikonomovic ◽  
David C. Bloom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Three Dimensional ◽  
Amyloid Plaque ◽  
Neuronal Cultures ◽  
Suitable Model ◽  
Infected Cells ◽  
Hsv 1

Alzheimer's disease is a progressive neurodegenerative disease characterized neuropathologically by presence of extracellular amyloid plaques composed of fibrillar amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles. Post-mortem and in vivo studies implicate HSV-1 infection in the brain as a precipitating factor in disease/pathology initiation. HSV-1 infection of two-dimensional (2D) neuronal cultures causes intracellular accumulation of Aβ42 peptide, but these 2D models do not recapitulate the three-dimensional (3D) architecture of brain tissue. We employed human induced pluripotent stem cells (hiPSCs) to compare patterns of Aβ42 accumulation in HSV-1 infected 2D (neuronal monolayers) and 3D neuronal cultures (brain organoids). Akin to prior studies, HSV-1-infected 2D cultures showed Aβ42 immunoreactivity in cells expressing the HSV-1 antigen ICP4 (ICP4+). Conversely, accumulation of Aβ42 in ICP4+ cells in infected organoids was rarely observed. These results highlight the importance of considering 3D cultures to model host-pathogen interaction. IMPORTANCE The “pathogen” hypothesis of Alzheimer’s disease (AD) proposes that brain HSV-1 infection could be an initial source of amyloid beta (Aβ) peptide-containing amyloid plaque development. Aβ accumulation was reported in HSV-1-infected 2D neuronal cultures and neural stem cell cultures, as well as in HSV-1-infected 3D neuronal culture models. The current study extends these findings by showing different patterns of Aβ42 accumulation following HSV-1 infection of 2D compared to 3D neuronal cultures (brain organoids). Specifically, 2D neuronal cultures showed Aβ42-immunoreactivity mainly in HSV-1-infected cells and only rarely in uninfected cells or infected cells exposed to antivirals. Conversely, 3D brain organoids showed accumulation of Aβ42 mainly in non-infected cells surrounding HSV-1-infected cells. We suggest that because brain organoids better recapitulate architectural features of a developing brain than 2D cultures, they may be a more suitable model to investigate the involvement of HSV-1 in the onset of AD pathology.

GINKGETIN AMELIORATES NEUROPATHOLOGICAL CHANGES IN APP/PS1 TRANSGENICAL MICE MODEL

2015 ◽  
pp. 1-6
Author(s):  
Y.-Q. Zeng ◽  
Y.-J. Wang ◽  
X.-F. Zhou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Biological Properties ◽  
Amyloid Angiopathy ◽  
Amyloid Beta Protein ◽  
Mice Model ◽  
Cerebral Microhemorrhage ◽  
The Brain

The extracellular accumulation of amyloid beta protein (Aβ), reactive gliosis and cerebral amyloid angiopathy (CAA) play critical roles in the pathogenesis of Alzheimer’s disease (AD). Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported to exhibit strong neuroprotection against cytotoxic insults induced by oxidative stress and amyloid beta, but it remains unclear whether ginkgetin has therapeutic effect on Alzheimer’s disease (AD) in vivo. In the present study, we investigated 9 months treatment effects of ginkgetin diet in APP/PS1 mice. Our results show that ginkgetin can significantly reduce plasma Aβ levels 59% and Aβ plaque 51% in the brain of APP/PS1 transgenic mice (P<0.05), effectively inhibits cerebral microhemorrhage 69% (P<0.05), significantly decreases astrogliosis 50% and ameliorate inflammation (P<0.05), exhibits several biological properties for AD.

The Precuneus – A Witness for Excessive Aβ Gathering in Alzheimer’s Disease Pathology

2018 ◽  
Vol 18 (5-6) ◽  
pp. 302-309 ◽  
Author(s):  
Gayane Aghakhanyan ◽  
Andrea Vergallo ◽  
Marta Gennaro ◽  
Sara Mazzarri ◽  
Federica Guidoccio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Duration ◽  
Standardized Uptake Value ◽  
Positive Association ◽  
Analysis Of Covariance ◽  
Qualitative Assessment ◽  
Control Group ◽  
Positron Emission

Evidence of cortical beta-amyloid (Aβ) load, assessed by Aβ positron emission tomography (Aβ-PET), is an established in vivo biomarker of Alzheimer’s disease (AD)-related pathophysiology. Qualitative assessment of Aβ-PET provides binary information; meanwhile semiquantitative approaches require a parcellation of PET image either manually or by placement of atlas-based volumes of interest. We supposed that a whole-brain approach with voxel-by-voxel standardized uptake value ratio (SUVr) parametric images may better elucidate the spatial trajectories of Aβ burden along the continuum of AD. Methods: We recruited 32 subjects with a diagnosis of probable AD dementia (ADD, n = 20) and mild cognitive impairment due to AD (MCI-AD, n = 12) according to the NIA-AA 2011 criteria. We also enrolled a control group of 6 cognitively healthy individuals (HCs) with preserved cognitive functions and negative Aβ-PET scan. The PET images were spatially normalized using the AV45 PET template in the MNI brain space. Subsequently, parametric SUVr images were calculated using the whole cerebellum as a reference region. A voxel-wise analysis of covariance was used to compare (between groups) the Αβ distribution pattern considering age as a nuisance covariate. Results: Both ADD and MCI-AD subjects showed a widespread increase in radiotracer uptake when compared with HC participants (p < 0.001, uncorrected). After applying a multiple comparison correction (p < 0.05, corrected), a relative large cluster of increased [18F]-flor­betapir uptake was observed in the precuneus in the ADD and MCI-AD groups compared to HCs. Voxel-wise regression analysis showed a significant positive linear association between the voxel-wise SUVr values and the disease duration. Conclusions: The voxel-wise semiquantitative analysis shows that the precuneus is a region with higher vulnerability to Aβ depositions when compared to other cortical regions in both MCI-AD and ADD subjects. We think that the precuneus is a promising PET-based outcome measure for clinical trials of drugs targeting brain Aβ. We found a positive association between the overall Aβ-PET SUVr and the disease duration suggesting that the region-specific slow saturation of Aβ deposition continuously takes place as the disease progresses.

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