Survival of Cultured Neurons from Amyloid Precursor Protein Knock-Out Mice against Alzheimer’s Amyloid-β Toxicity and Oxidative Stress

White, Anthony R.; Zheng, Hui; Galatis, Denise; Maher, Frances A.; Hesse, Lars; Multhaup, Gerd; Beyreuther, Konrad; Masters, Colin L.; Cappai, Roberto

doi:10.1523/jneurosci.18-16-06207.1998

Cited by 85 publications

(76 citation statements)

References 56 publications

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“…APP belongs to a multigene family that includes the two amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2) (4,(43)(44)(45). Most of the functional domains and structural motifs found in APP are also present in APLPs (particularly APLP2) (60), suggesting that they may share common biological functions in neurons. Using the monoclonal antibody 22C11, several studies have reported that this antibody cannot discriminate between APP and APLP2 (45,60,61).…”

Section: App-ab-dependent Pcd Is Distinct From Apoptosis-thismentioning

confidence: 99%

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Mbebi¹,

Sée²,

Mercken³

et al. 2002

Journal of Biological Chemistry

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The aberrant metabolism of ␤-amyloid precursor protein (APP) and the progressive deposition of its derived fragment ␤-amyloid peptide are early and constant pathological hallmarks of Alzheimer's disease. Because APP is able to function as a cell surface receptor, we investigated here whether a disruption of the normal function of APP may contribute to the pathogenic mechanisms in Alzheimer's disease. To this aim, we generated a specific chicken polyclonal antibody directed against the extracellular domain of APP, which is common with the ␤-amyloid precursor-like protein type 2. Exposure of cultured cortical neurons to this antibody (APP-Ab) induced cell death preceded by neurite degeneration, oxidative stress, and nuclear condensation. Interestingly, caspase-3-like protease was not activated in this neurotoxic action suggesting a different mode of cell death than classical apoptosis. Further analysis of the molecular mechanisms revealed a calpain-and calcineurindependent proteolysis of the neuroprotective calcium/ calmodulin-dependent protein kinase IV and its nuclear target protein cAMP responsive element binding protein. These effects were abolished by the G protein inhibitor pertussis toxin, strongly suggesting that APP binding operates via a GTPase-dependent pathway to cause neuronal death. Alzheimer's disease (AD)1 is a devastating neurodegenerative disorder characterized by deposition of ␤-amyloid (A␤) plaques, accumulation of intracellular neurofibrillary tangles, and neuronal cell loss (1). A␤ peptide is generated by proteolysis of the amyloid precursor protein (APP), which is the product of a gene located on human chromosome 21 and on mouse chromosome 16. APP is expressed in most mammalian tissues (2, 3) and is present in at least 10 different spliced variants (4). In the brain, the major isoform generating A␤ is a peptide consisting of 695 residues that contains a single transmembrane domain (5). Although the physiological role of APP is still unclear, several studies have suggested that it is implicated in important physiological functions of neurons, such as neurite outgrowth, synaptogenesis, cell substrate adhesion and neuronal survival (for review see Ref. 6).Up to now, most of the research has been focused on the toxicity of A␤ peptide related to AD. A␤ has been reported to exert a variety of toxic effects on neurons both in vitro (7,8) and in vivo (9). However, it has been reported that mice overproducing A␤1-42 extracellularly showed no neuronal loss (10), thus suggesting that A␤ peptide seems not to be the only constituent in neurotoxicity associated to AD. Previous studies have demonstrated that overexpression of full-length APP induced degeneration of postmitotic neurons derived from embryonal carcinoma cells (11). Moreover, intracellular accumulation of wild-type APP in the rat hippocampus caused a specific type of neuronal degeneration in vivo in the absence of extracellular A␤ deposition (12), and viral vector-mediated overexpression of wild-type APP induced apoptosis-like death of neurons...

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Section: App-ab-dependent Pcd Is Distinct From Apoptosis-thismentioning

confidence: 99%

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Mbebi¹,

Sée²,

Mercken³

et al. 2002

Journal of Biological Chemistry

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“…Cortical cultures were prepared as described previously (White et al, 1998). In brief, embryonic day 14 C57BL6Jx 129sv mouse cortices were removed, dissected free of meninges, and dissociated in 0.025% (wt/vol) trypsin.…”

Section: Primary Neuronal Culturesmentioning

confidence: 99%

“…At day 5 in vitro, BSO (0.01-I00 p M ) was added to the culture medium with or without CuCl,,FeCI,,or FeC1,. After 16 h at 37"C, cell viability was determined using the MTT assay as described previously (White et al, 1998). We have found that the MTT assay provides an accurate indication of neuronal viability under the conditions used and compares favorably with other viability assays such as Alamar Blue method.…”

Section: Gsh Depletion and Transition Metal Treatmentmentioning

confidence: 99%

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

White

Bush

Beyreuther

et al. 1999

Journal of Neurochemistry

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Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-l -nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-p (Ap) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Ap25-35 in the presence or absence of Cu or Fe. Ap25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Ap to perturb neuronal GSH homeostasis.Ap25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.

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“…In APP-and APLP2-knockout mice, Cu levels were found increased in cerebral cortex and liver, whereas overexpression of APP was reported to result in significantly reduced Cu levels in the Tg2576 line (17)(18)(19). Depending on the conservation of the CuBD, Cu was also found to influence APP processing in cells when Cu greatly reduced the levels of amyloid A␤, and caused an increase in the secretion of the APP ectodomain (20,21).…”

mentioning

confidence: 99%

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Bayer

Schäfer

Simons

et al. 2003

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

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317

255

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The Cu-binding ␤-amyloid precursor protein (APP), and the amyloid A␤ peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in A␤ levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS A␤ before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

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Survival of Cultured Neurons from Amyloid Precursor Protein Knock-Out Mice against Alzheimer’s Amyloid-β Toxicity and Oxidative Stress

Cited by 85 publications

References 56 publications

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Amyloid Precursor Protein Family-induced Neuronal Death Is Mediated by Impairment of the Neuroprotective Calcium/Calmodulin Protein Kinase IV-dependent Signaling Pathway

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

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