Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/PS1 transgenic mice

Blanchard, Véronique; Moussaoui, Saliha; Czech, Christian; Touchet, Nathalie; Bonici, Bruno; Planche, Michel; Canton, Thierry; Jedidi, Iness; Gohin, M.; Wirths, Oliver; Bayer, Thomas A.; Langui, Dominique; Duyckaerts, Charles; Tremp, Günter; Pradier, Laurent

doi:10.1016/s0014-4886(03)00252-8

Cited by 263 publications

(281 citation statements)

References 66 publications

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“…Most of these oxidized neurites surrounding Aβ plaques formed dystrophic varicosities, which are likely to be axonal abnormalities (21). Oxidation in dystrophic neurites has been reported by using immunohistochemistry and includes lipid peroxidation and the accumulation of a variety of mitochondrial stress markers (22,23). Furthermore, structural alteration of dendrites that included a beaded appearance was also observed in oxidized neurites near Aβ plaques (Fig.…”

Section: Resultsmentioning

confidence: 87%

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Xie

Hou

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

143

120

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Neuronal loss is the ultimate outcome in a variety of neurodegenerative diseases and central nerve system disorders. Understanding the sequelae of events that leads to cell death would provide insight into neuroprotective approaches. We imaged neurons in the living brain of a mouse model of Alzheimer's disease that overexpresses mutant human amyloid precursor protein and presenilin 1 and followed the death of individual neurons in real time. This mouse model exhibited limited neurodegeneration and atrophy, but we were able to identify a small fraction of vulnerable cells that would not have been detectable by using standard approaches. By exploiting a genetically encoded reporter of oxidative stress, we identified susceptible neurons by their increased redox potential. The oxidative stress was most dramatic in neurites near plaques, propagated to cell bodies, and preceded activation of caspases that led to cell death within 24 h. Thus, local oxidative stress surrounding plaques contributes to longrange toxicity and selective neuronal death in Alzheimer's disease.in vivo imaging | reduction-oxidation sensitive GFP A lzheimer's disease (AD) is underscored by neurodegeneration and is the most common form of dementia. The pathological hallmarks of this disease include amyloid plaques, neurofibrillary tangles, and neuronal loss. Early-onset familial AD is caused by genetic mutations of amyloid precursor protein (APP) or presenilin 1 and 2 (PS1 and PS2). Although recent genetic studies have revealed risk factors for late onset AD, the pathogenic pathways for sporadic AD remain largely unknown. The development of mouse models of AD that develop senile plaques similar to those found in AD patients was a critical step in identifying the role of amyloid β (Aβ) on neuronal function. A major disappointment of most of the mouse models is the lack of overt neuronal loss that is a hallmark of the human disease. Many, in fact, have used this lack of neuronal death as evidence that amyloid is not relevant to dementia in AD. We and others (1-4) have identified structural and functional alterations of neurons in the brains of APP mice that implicate amyloid-mediated toxicity, but we have never detected neuronal death. The ability to monitor cell death in an experimental model provides the opportunity to intervene with neuroprotective agents that could be applied to the spectrum of neurodegenerative diseases and CNS disorders.We were able to identify vulnerable cells by quantitatively imaging the redox potential of neurons in the living brain. Our hypothesis was that amyloid-mediated increases in oxidative stress are the initiators of the toxic cascade that leads to cell loss. Accumulating evidence supports a role for oxidative stress in the pathogenesis of neuronal degeneration and death in AD (5-8). The evidence supporting oxidative stress in AD comes largely from postmortem samples and includes increased lipid peroxidation, decreased polyunsaturated fatty acids (9-12), increased protein oxidation (13,14), and DNA oxidation (15, ...

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Section: Resultsmentioning

confidence: 87%

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Xie

Hou

Jiang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

143

120

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“…This is due to the fact that mutations in PS1 have been shown to enhance ␥-secretase activity toward elevated A␤42 generation. 74 -76 The A␤42/A␤ ratio was approximately 0.2 in the APP751 SL mice and approximately 0.4 in the APP751 SL /PS1 M146L mice investigated here 11 and was increased to approximately 0.85 in APP SL /PS1KI mice that showed profound hippocampal neuron loss and intraneuronal accumulation of A␤ already at 10 months of age. 70 We hypothesize that in the hippocampus of APP SL /PS1KI mice, profound SIPB loss will also be found in regions free of A␤ deposits, and the comparison of results from APP751 SL / PS1 M146L mice and APP SL /PS1KI mice will provide novel insights into the impact of transgenic expression and "knock-in" expression of mutations of PS1 on impairments of synaptic integrity in AD.…”

Section: Alterations In Sipb Densities and Sipb Numbers In App751 Sl mentioning

confidence: 74%

“…Previous reports have shown that intraneuronal A␤ preceded the formation of A␤ deposits in APP751 SL /PS1 M146L mice 9 and that elevated levels of intraneuronal A␤ were associated with several alterations in normal cell homeostasis. 11,14,64,70 Moreover, intraneuronal A␤ has been reported to substantially affect synaptic function 26 and integrity. 71 6) A chronic inflammation status.…”

Section: Alterations In Sipb Densities and Sipb Numbers In App751 Sl mentioning

confidence: 99%

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

Rutten

Kolk

Schäfer

et al. 2005

The American Journal of Pathology

107

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Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD).Recently, we observed substantial age-related hippocampal neuron loss in APP751 SL /PS1 M146L transgenic mice but not in PS1 M146L mice. Here, we investigated APP751 SL mice, PS1 M146L mice, and APP751 SL / PS1 M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysinimmunoreactive presynaptic boutons (SIPBs). Wildtype mice, APP751 SL mice and PS1 M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751 SL mice and PS1 M146L mice showed age-related SIPB loss within SR. Importantly, APP751 SL /PS1 M146L mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular A␤ deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. Alzheimer's disease (AD) is a progressive neurodegenerative disorder comprising cognitive and memory deterioration, progressive impairment of activities of daily living, and several neuropsychiatric symptoms. 1 The neuropathology of AD is characterized by disturbances in neural circuits, such as loss of neurons and synapses, and by protein aggregations of ␤-amyloid and hyperphosphorylated tau. 2-4 Accumulating evidence has indicated a crucial role for failure and loss of synapses in AD pathophysiology. 2,4,[5][6][7] Postmortem morphological studies on AD neuropathology have demonstrated significantly reduced synaptic connectivity in brain regions such as the neocortex and hippocampus. 3,6,7 Reductions in synaptic densities showed a strong correlation with cognitive decline in AD. 5 However, the reasons for the reduced connectivity in AD remain poorly understood. 8 According to the "␤-amyloid (A␤) hypothesis of AD," A␤ accumulation is the primary driving force in AD pathogenesis. This hypothesis is supported by the fact that mutations in the amyloid precursor protein (APP) and in presenilin (PS) 1 and PS2, causing early-onset cases of AD, modify APP processing and result in enhanced generation of A␤. 4 We have developed a transgenic mouse model of AD expressing human mutant APP751 (carrying the Swedish and London mutations KM670/671NL and

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“…These bigenic mice were obtained (see Blanchard et al, 2003) by crossing homozygous PS1 mice (expressing human mutant PS1[M146L] under HMGCoA reductase promoter) to hemizygous APP751SL mice (expressing human mutant APP751 carrying the Swedish [KM670/671NL] and London [V717I] mutations under the control of the Thy1 promoter). We have previously characterized this APP/PS1 transgenic model (Baglietto‐Vargas et al, 2010; Jimenez et al, 2008; Ramos et al, 2006; Sanchez‐Varo et al, 2012; Torres et al, 2012; Trujillo‐Estrada et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

Gómez-Arboledas

Dávila

Sánchez-Mejías

et al. 2017

Glia

160

126

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Reactive astrogliosis, a complex process characterized by cell hypertrophy and upregulation of components of intermediate filaments, is a common feature in brains of Alzheimer's patients. Reactive astrocytes are found in close association with neuritic plaques; however, the precise role of these glial cells in disease pathogenesis is unknown. In this study, using immunohistochemical techniques and light and electron microscopy, we report that plaque‐associated reactive astrocytes enwrap, engulf and may digest presynaptic dystrophies in the hippocampus of amyloid precursor protein/presenilin‐1 (APP/PS1) mice. Microglia, the brain phagocytic population, was apparently not engaged in this clearance. Phagocytic reactive astrocytes were present in 35% and 67% of amyloid plaques at 6 and 12 months of age, respectively. The proportion of engulfed dystrophic neurites was low, around 7% of total dystrophies around plaques at both ages. This fact, along with the accumulation of dystrophic neurites during disease course, suggests that the efficiency of the astrocyte phagocytic process might be limited or impaired. Reactive astrocytes surrounding and engulfing dystrophic neurites were also detected in the hippocampus of Alzheimer's patients by confocal and ultrastructural analysis. We posit that the phagocytic activity of reactive astrocytes might contribute to clear dysfunctional synapses or synaptic debris, thereby restoring impaired neural circuits and reducing the inflammatory impact of damaged neuronal parts and/or limiting the amyloid pathology. Therefore, potentiation of the phagocytic properties of reactive astrocytes may represent a potential therapy in Alzheimer's disease.

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Time sequence of maturation of dystrophic neurites associated with Aβ deposits in APP/PS1 transgenic mice

Cited by 263 publications

References 66 publications

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Rapid cell death is preceded by amyloid plaque-mediated oxidative stress

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

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