P2-314

2013

Recent human trials of treatments for Alzheimer’s disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-b (Ab) plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Ab were essentially the last pathological changes, w...

PLOS ONE, 2013

Recent human trials of treatments for Alzheimer's disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-b (Ab) plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Ab were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Ab. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression.

Journal of Neuroinflammation, 2014

Background: Beyond cognitive decline, Alzheimer's disease (AD) is characterized by numerous neuropathological changes in the brain. Although animal models generally do not fully reflect the broad spectrum of disease-specific alterations, the APP SL mouse model is well known to display early plaque formation and to exhibit spatial learning and memory deficits. However, important neuropathological features, such as neuroinflammation and lipid peroxidation, and their progression over age, have not yet been described in this AD mouse model. Methods: Hippocampal and neocortical tissues of APP SL mice at different ages were evaluated. One hemisphere from each mouse was examined for micro-and astrogliosis as well as concomitant plaque load. The other hemisphere was evaluated for lipid peroxidation (quantified by a thiobarbituric acid reactive substances (TBARS) assay), changes in Aβ abundance (Aβ38, Aβ40 and Aβ42 analyses), as well as determination of aggregated Aβ content (Amorfix A 4 assay). Finally, correlation analyses were performed to illustrate the time-dependent correlation between neuroinflammation and Aβ load (soluble, insoluble, fibrils), or lipid peroxidation, respectively. Results: As is consistent with previous findings, neuroinflammation starts early and shows strong progression over age in the APP SL mouse model. An analyses of concomitant Aβ load and plaque deposition revealed a similar progression, and high correlations between neuroinflammation markers and soluble or insoluble Aβ or fibrillar amyloid plaque loads were observed. Lipid peroxidation, as measured by TBARS levels, correlates well with neuroinflammation in the neocortex but not the hippocampus. The hippocampal lipid peroxidation correlated strongly with the increase of LOC positive fiber load, whereas neocortical TBARS levels were unrelated to amyloidosis. Conclusions: These data illustrate for the first time the progression of major AD related neuropathological features other than plaque load in the APP SL mouse model. Specifically, we demonstrate that microgliosis and astrocytosis are prominent aspects of this AD mouse model. The strong correlation of neuroinflammation with amyloid burden and lipid peroxidation underlines the importance of these pathological factors for the development of AD. The new finding of a different relation of lipid peroxidation in the hippocampus and neocortical regions show that the model might contribute to the understanding of complex pathological mechanisms and their interplay in AD.

2000

The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgenepositive (Tgϩ) and negative (TgϪ) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1␤ and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of ␤-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble A␤. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of antiphosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Alzheimer's Research & Therapy, 2022

Background: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (x c-), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [ 18 F]DPA-714 and [ 18 F]FSPG for their ability to detect TSPO and x c biomarkers, respectively, in the 5xFAD mouse model for AD. Methods: Expression of TSPO and x c system was assessed longitudinally (2-12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [ 18 F]DPA-714 and [ 18 F] FSPG. In parallel, in the same mice, amyloid-β plaque deposition was assessed with the amyloid PET radiotracer [ 18 F] florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and x c in microglia/ macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice. Results: PET studies showed a significant increase in the uptake of [ 18 F]DPA-714 and [ 18 F]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with Aβ plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of x c in non-glial cells of 5xFAD mice. Additionally, the results show that Aβ plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls. Conclusions: TSPO and x c overexpression can be assessed by [ 18 F]DPA-714 and [ 18 F]FSPG, respectively, and correlate with the level of Aβ plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression.

Journal of Magnetic Resonance Imaging, 2006

PurposeTo assess the development of β-amyloid (Aβ) plaques in the brain with age in the transgenic mouse model of Alzheimer's disease (AD) pathology by in vivo magnetic resonance microimaging (μMRI).To assess the development of β-amyloid (Aβ) plaques in the brain with age in the transgenic mouse model of Alzheimer's disease (AD) pathology by in vivo magnetic resonance microimaging (μMRI).Materials and MethodsLive transgenic mice (Tg2576) and nontransgenic littermates (control) were studied at regular intervals between the ages of 12 and 18 months. Plaques were visualized using a T2-weighted rapid acquisition with relaxation enhancement (RARE) sequence. Changes in T2 relaxation times were followed using a multislice multiecho (MSME) sequence. Plaque load and numerical density in MR images were calculated using SCIL image software.Live transgenic mice (Tg2576) and nontransgenic littermates (control) were studied at regular intervals between the ages of 12 and 18 months. Plaques were visualized using a T2-weighted rapid acquisition with relaxation enhancement (RARE) sequence. Changes in T2 relaxation times were followed using a multislice multiecho (MSME) sequence. Plaque load and numerical density in MR images were calculated using SCIL image software.ResultsAβ plaques were clearly detected with the T2-weighted RARE sequence in the hippocampal and cortical regions of the brain of Tg2576 mice but not in control mice. Following the plaque development in the same animals with age showed that plaque area, number, and size increased markedly, while T2 relaxation time showed a decreasing trend with age.Aβ plaques were clearly detected with the T2-weighted RARE sequence in the hippocampal and cortical regions of the brain of Tg2576 mice but not in control mice. Following the plaque development in the same animals with age showed that plaque area, number, and size increased markedly, while T2 relaxation time showed a decreasing trend with age.ConclusionThese results demonstrate that μMRI is a viable method for following the development of Aβ plaques in vivo, and suggest that this method may be feasible for assessing the effect of therapeutic interventions over time in the same animals. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.These results demonstrate that μMRI is a viable method for following the development of Aβ plaques in vivo, and suggest that this method may be feasible for assessing the effect of therapeutic interventions over time in the same animals. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.

NeuroImage. Clinical, 2017

Transgenic animal models of Aβ pathology provide mechanistic insight into some aspects of Alzheimer disease (AD) pathology related to Aβ accumulation. Quantitative neuroimaging is a possible aid to improve translation of mechanistic findings in transgenic models to human end phenotypes of brain morphology or function. Therefore, we combined MRI-based morphometry, MRS-based NAA-assessment and quantitative histology of neurons and amyloid plaque load in the APPswe/PS1dE9 mouse model to determine the interrelationship between morphological changes, changes in neuron numbers and amyloid plaque load with reductions of NAA levels as marker of neuronal functional viability. The APPswe/PS1dE9 mouse showed an increase of Aβ plaques, loss of neurons and an impairment of NAA/Cr ratio, which however was not accompanied with brain atrophy. As brain atrophy is one main characteristic in human AD, conclusions from murine to human AD pathology should be drawn with caution.

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

The brain in Alzheimer's disease (AD) shows a chronic inflammatory response characterized by activated glial cells and increased expression of cytokines and complement factors surrounding amyloid deposits. Several epidemiological studies have demonstrated a reduced risk for AD in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), prompting further inquiries about how NSAIDs might influence the development of AD pathology and inflammation in the CNS. We tested the impact of chronic orally administered ibuprofen, the most commonly used NSAID, in a transgenic model of AD displaying widespread microglial activation, age-related amyloid deposits, and dystrophic neurites. These mice were created by overexpressing a variant of the amyloid precursor protein found in familial AD. Transgenepositive (Tgϩ) and negative (TgϪ) mice began receiving chow containing 375 ppm ibuprofen at 10 months of age, when amyloid plaques first appear, and were fed continuously for 6 months. This treatment produced significant reductions in final interleukin-1␤ and glial fibrillary acidic protein levels, as well as a significant diminution in the ultimate number and total area of ␤-amyloid deposits. Reductions in amyloid deposition were supported by ELISA measurements showing significantly decreased SDS-insoluble A␤. Ibuprofen also decreased the numbers of ubiquitin-labeled dystrophic neurites and the percentage area per plaque of antiphosphotyrosine-labeled microglia. Thus, the anti-inflammatory drug ibuprofen, which has been associated with reduced AD risk in human epidemiological studies, can significantly delay some forms of AD pathology, including amyloid deposition, when administered early in the disease course of a transgenic mouse model of AD.

Academia Letters, 2021

Striking a balance between decongesting prisons and successful offender reintegration: a critical analysis of massive offender releases in mitigating against spread of COVID 19 in prisons Phaello Malataliana The World Health Organization (WHO) has deemed the Coronavirus (COVID-19) a world pandemic which has indeed brought disruptions to all spheres of life. The pandemic has brought forth a debate on the rights of the most vulnerable groups of the society inclusive of prisoners. Correctional institutions and prisons are generally characterized by among other things overcrowding and unsanitary conditions which have been highlighted by medical experts as that which can perpetuate the spread of the virus. Medical experts and human rights defenders or lawyers have called for reductions in incarceration levels to limit overcrowding and protect those individuals in custody who are at high risk of serious illness and death from COVID-19. Generally, correctional institutions and or prisons are mandated to provide safe custody and rehabilitation of inmates and further ensuring that they go back to their societies as law abiding citizens. The ultimate measure of successful rehabilitation and reintegration of inmates is low recidivism rates by those who have gone through the correctional system and this principle is highlighted by Nelson Mandela Rules (Rule 4). In emphasizing the importance of community involvement in prisoners' reintegration, Basic Principles for Treatment of Offenders states that 'With the participation and help of the community and social institutions, and with due regard to the interests of victims, favorable conditions shall be created for the reintegration of the ex-prisoner into society under the best possible conditions'. Notwithstanding the merits of this principle, we need to take into con

Film Quarterly, 2024

Alex Garland’s Civil War imagines an America in which political differences have augmented into warring factions, split across varying ideological lines. Kirsten Dunst plays Lee Smith, a renowned photojournalist whom FQ columnist Ramzi Fawaz places in a lineage of white women intellectuals, from Hannah Arendt to Joan Didion, whose reportage documented the social and political atrocities of 20th century. Their observational style is described by literary theorist Deborah Nelson as “unsentimental”: a methodology for how to approach the violence of everyday life in as objective a manner as possible. But what value does unsentimentality have in a political landscape in which politics and the ability to objectively understand competing points of view is clouded by identity, and when being a witness to recurring scenes of intense violence becomes too much to bear?