High throughput object-based image analysis of β-amyloid plaques in human and transgenic mouse brain

Samaroo, Harry; Opsahl, Alan; Schreiber, Jan; Marconi, Michael; Qian, Jessie; Carvajal‐Gonzalez, Santos; Tate, Barbara; Milici, Anthony J.; Bales, Kelly R.; Stephenson, Diane

doi:10.1016/j.jneumeth.2011.10.003

Cited by 21 publications

(19 citation statements)

References 50 publications

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“…An earlier study reported that diffuse amyloid plaques begin to appear in the hippocampus and cerebral cortex of APP/PS1 mice at 3 months old (Trinchese et al 2004). Subsequent studies have revealed an age-dependent pattern of Aβ burden in this AD model (Samaroo et al 2012;Janus et al 2015). By use of thioflavin-S and 6E10 immunostaining, we found that 24-month-old APP/PS1 mice versus their 20-month counterparts have a higher percentage of area occupied by thioflavin-Slabeled core plaques (7.24 vs. 3.15 %) or 6E10-labeled diffusing plaques (3.02 vs. 3.65 %) in the hippocampus .…”

Section: Discussionmentioning

confidence: 85%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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Transgenic APPSwe/PS1dE9 (APP/PS1) mice that overproduce amyloid beta (Aβ) are extensively used in the studies of pathogenesis and experimental therapeutics and new drug screening for Alzheimer's disease (AD). However, most of the current literature uses young or adult APP/PS1 mice. In order to provide a broader view of AD-like phenotype of this animal model, in this study, we systematically analyzed behavioral and pathological profiles of 24-month-old male APP/ PS1 mice. Aged APP/PS1 mice had reference memory deficits as well as anxiety, hyperactivity, and social interaction impairment. Consistently, there was obvious deposition of amyloid plaques in the dorsal hippocampus with decreased expression of insulin-degrading enzyme, a proteolytic enzyme responsible for degradation of intracellular Aβ. Furthermore, decreases in hippocampal volume, neuronal number and synaptophysin expression, and astrocyte atrophy were also observed in aged APP/PS1 mice. This finding suggests that aged APP/PS1 mice can well replicate cognitive and noncognitive behavioral abnormalities, hippocampal atrophy, and neuronal and astrocyte degeneration in AD patients, to enable more objective and refined preclinical evaluation of therapeutic drugs and strategies for AD treatment.

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Section: Discussionmentioning

confidence: 85%

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Huang

Nie

Cao

et al. 2016

AGE

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“…To determine whether MAGL contributes to eicosanoid production, neuroinflammation and pathophysiology in the PS1/APP + mouse brain, we bred MAGL-disrupted ( Mgll −/− ) (Chanda et al, 2010) and PS1/APP + transgenic mice (Samaroo et al, 2012) to generate 4 genotypes for our studies: Mgll +/+ /PS1/APP − , Mgll +/+ /PS1/APP + , Mgll −/− /PS1/APP − , and Mgll −/− /PS1/APP + . We found that Mgll −/− /PS1/APP − and Mgll −/− /PS1/APP + mice presented higher levels of the MAGL substrate 2-AG (C20:4 MAG) and dramatically reduced levels of AA (C20:4 FFA), prostaglandins (PGE2 and PGD2), and thromboxane B2 (TXB2) in their brains compared to their Mgll +/+ /PS1/APP − and Mgll +/+ / PS1/APP + counterparts, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mgll −/− mice (Chanda et al, 2010) were crossed with PS1/APP + transgenic mice (Samaroo et al, 2012) to create the 4 genotypes used in these studies: Mgll +/+ /PS1/APP − , Mgll +/+ /PS1/APP + , Mgll −/− /PS1/APP − , and Mgll −/− /PS1/APP + . All experiments were conducted in accordance with Pfizer’s IACUC guidelines.…”

Section: Methodsmentioning

confidence: 99%

A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

et al. 2012

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Summary Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer’s disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL) hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid βlevels and plaques, in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a heretofore unrecognized role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology, and put forth MAGL inhibitors as a potential next-generation strategy for combatting AD.

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“…Such files can then be used for high-throughput, sophisticated image analyses, which offer quantitation capabilities that far exceed those that can be achieved manually in terms of reproducibility, unbiased image recognition algorithms and sheer volume. Previous studies have demonstrated some of the advantages of digital image analysis within AD research; either through montaged still images (34) or a variety of digital slide systems (35, 36). One such software package is Aperio’s Genie Histologic Pattern Recognition Tool (37).…”

Section: Introductionmentioning

confidence: 99%

Digital Pathology and Image Analysis for Robust High-Throughput Quantitative Assessment of Alzheimer Disease Neuropathologic Changes

Neltner

Abner

Schmitt

et al. 2012

J Neuropathol Exp Neurol

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Quantitative neuropathologic methods provide information that is important for both research and clinical applications. The technological advancement of digital pathology and image analysis offers new solutions to enable valid quantification of pathological severity that is reproducible between raters regardless of experience. Using an Aperio ScanScope XT and its accompanying image analysis software, we designed algorithms for quantitation of amyloid and tau pathologies on 65 β-amyloid (6F/3D antibody) and 48 phospho-tau (PHF-1)-immunostained sections of human temporal neocortex. Quantitative digital pathologic data were compared with manual pathology counts. There were excellent correlations between manually counted and digitally analyzed neuropathologic parameters (R2 values 0.56-0.72). Data were highly reproducible among 3 participants with varying degrees of expertise in neuropathology (Intra-class correlation coefficient values >0.910). Digital quantification also provided additional parameters, including average plaque area, which show statistically significant differences when samples are stratified according to APOE allele status (average plaque area 380.9 μm2 in ApoE ε4 carriers vs. 274.4 μm2 for non-carriers, p < 0.001). Thus, digital pathology offers a rigorous and reproducible method for quantifying AD neuropathologic changes and may provide additional insight into morphologic characteristics that were previously more challenging to assess due to technical limitations.

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High throughput object-based image analysis of β-amyloid plaques in human and transgenic mouse brain

Cited by 21 publications

References 50 publications

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

Digital Pathology and Image Analysis for Robust High-Throughput Quantitative Assessment of Alzheimer Disease Neuropathologic Changes

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