Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer’s disease

Adamec, Emil; Mohan, Panaiyur S.; Cataldo, Anne M.; Vonsattel, Jean Paul; Nixon, Ralph A.

doi:10.1016/s0306-4522(00)00281-5

Cited by 104 publications

(48 citation statements)

References 69 publications

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“…Therefore, cathepsin D likely promotes the phagocytosis and lysosomal activity of macrophages/microglia in the SCI lesion. The neuronal and glial expressions of cathepsin D remained unclear, although the expression of cathepsin D has been reported to increase in the neuronal cells of patients with neurodegenerative diseases, including Alzheimer's disease [1]. In this study, constitutive cathepsin D expression in neurons and gliocytes was observed in the spinal cords of the normal rats.…”

Section: Immunohistochemical Localization Of Cathepsin D In Rat Scimentioning

confidence: 64%

Immunohistochemical Study of Cathepsin D in the Spinal Cords of Rats with Clip Compression Injury

Moon

LEE

KIM

et al. 2008

The Journal of Veterinary Medical Science

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ABSTRACT. This study examined the temporal expression of cathepsin D protein and its cellular localization in the spinal cords of rats after a clip compression injury to determine the involvement of cathepsin D in spinal cord injury (SCI). Western blot analysis showed a significant increase in the ~31-kDa active form of cathepsin D on days 4 and 7 after the SCI, while the level of the ~44-kDa inactive form remained relatively unchanged. Immunohistochemistry revealed cathepsin D with constitutive localization in most neurons and some gliocytes in the normal spinal cord to be intensely immuno-detected primarily in CD68-positive activated macrophages/microglia in the SCI lesions. Overall, these findings suggest that cathepsin D plays an important role in the phagocytosis and lysosomal activation of macrophages/microglia during the central nervous system inflammation caused by trauma. KEY WORDS: cathepsin D, clip compression injury, macrophages/microglia, spinal cord.

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Section: Immunohistochemical Localization Of Cathepsin D In Rat Scimentioning

confidence: 64%

Immunohistochemical Study of Cathepsin D in the Spinal Cords of Rats with Clip Compression Injury

Moon

LEE

KIM

et al. 2008

The Journal of Veterinary Medical Science

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“…Endosomal CD may be linked to A␤ formation, in that CD possesses inherent ␤-and -secretase activity, enzymes that are responsible for the cleavage of amyloid precursor protein into A␤ (31), although APP processing was shown previously to be unaffected by CD deficiency in mice (119). Increased levels and activity of CB and CD in AD brain have been shown to occur concomitant with lysosome proliferation (2,22,24,27,29) and may reflect a compensatory response to altered macroautophagy, but it is not clear whether such alterations serve a beneficial role to promote protein degradation or death signaling. In addition, both CB and CD have been localized extracellularly to amyloid plaque, which may indicate their potential to regulate plaque deposition (27,29).…”

Section: Oxidative Stress Autophagy and Lysosome Dysfunction In Cnsmentioning

confidence: 99%

Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death

Pivtoraiko

Stone

Roth

et al. 2009

Antioxidants & Redox Signaling

118

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Lysosomes critically regulate the pH-dependent catabolism of extracellular and intracellular macromolecules delivered from the endocytic/heterophagy and autophagy pathways, respectively. The importance of lysosomes to cell survival is underscored not only by their unique ability effectively to degrade metalloproteins and oxidatively damaged macromolecules, but also by the distinct potential for induction of both caspase-dependent and -independent cell death with a compromise in the integrity of lysosome function. Oxidative stress and free radical damage play a principal role in cell death induced by lysosome dysfunction and may be linked to several upstream and downstream stimuli, including alterations in the autophagy degradation pathway, inhibition of lysosome enzyme function, and lysosome membrane damage. Neurons are sensitive to lysosome dysfunction, and the contribution of oxidative stress and free radical damage to lysosome dysfunction may contribute to the etiology of neurodegenerative disease. This review provides a broad overview of lysosome function and explores the contribution of oxidative stress and autophagy to lysosome dysfunction-induced neuron death. Putative signaling pathways that either induce lysosome dysfunction or result from lysosome dysfunction or both, and the role of oxidative stress, free radical damage, and lysosome dysfunction in pediatric lysosomal storage disorders (neuronal ceroid lipofuscinoses or NCL/Batten disease) and in Alzheimer's disease are emphasized. Antioxid. Redox Signal. 11,[481][482][483][484][485][486][487][488][489][490][491][492][493][494][495][496]

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“…First, neurons from AD patients contain increased numbers of autophagosomes and lysosomes 15 and show increased expression of lysosomal hydrolases, 16 indicating activation of the autophagic-lysosomal system in this disorder. Second, Aβ generation has been detected within autophagic vacuoles following activation of macroautophagy.…”

Section: Introductionmentioning

confidence: 99%

Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells

et al. 2011

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) Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidantinduced apoptosis of cultured neuroblastoma cells, Autophagy, 7:12, 1528-1545 To link to this article: https://doi.org/10.4161/auto.7.12.18051 Do not distribute.Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells Keywords: Alzheimer disease, amyloid β-protein, amyloid precursor protein, apoptosis, autophagy, lysosomes, oxidative stressAbbreviations: 3MA, 3-methyladenine; AD, Alzheimer disease; ATG5, autophagy-related protein 5; Aβ, amyloid β-protein; APP, amyloid precursor protein; NH4Cl, ammonium chloride; APPwt, wild-type APP695; APPswe, Swedish KM670/671NL double mutation; α-APP, α-secretase processed APP; DAPT, LY-374973, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; DCF, carboxy-H 2 DCFDA; DAPI, 4' 6-diamidino-2-phenylindole; E64d, (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester, EST; HEK, human embryonic kidney; LAMP-2, lysosomal associated membrane protein-2; LC3, microtubule-associated protein 1 light chain 3; NFT, neurofibrillary tangles; RA, retinoic acid; ROS, reactive oxygen speciesIncreasing evidence suggests the toxicity of intracellular amyloid β-protein (Aβ) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days, and consequent activation of macroautophagy and accumulation of Aβ within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide additional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

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Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer’s disease

Cited by 104 publications

References 69 publications

Immunohistochemical Study of Cathepsin D in the Spinal Cords of Rats with Clip Compression Injury

Immunohistochemical Study of Cathepsin D in the Spinal Cords of Rats with Clip Compression Injury

Oxidative Stress and Autophagy in the Regulation of Lysosome-Dependent Neuron Death

Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells

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