G Protein-Mediated Neuronal DNA Fragmentation Induced by Familial Alzheimer's Disease-Associated Mutants of APP

Yamatsuji, Tomoki; Mizutani, Takashi; Okamoto, Takashi; Komatsuzaki, Katsumi; Takeda, Shuji; Fukumoto, Hiroaki; Iwatsubo, Takeshi; Suzuki, Nobuhiro; Asami-Odaka, Asano; Ireland, Scott; Kinane, T. Bernard; Giambarella, Ugo; Nishimoto, Ikuo

doi:10.1126/science.272.5266.1349

Cited by 217 publications

(173 citation statements)

References 39 publications

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“…This effect is probably not related to the physiological process of immunosenescence. In addition, apoptosis is a hallmark in brains derived from Alzheimer's patients, possibly associated with states of increased oxidative stress [8,45,49,52]. Similar alterations could also be detected in peripheral cells of AD patients [27,31].…”

Section: Discussionmentioning

confidence: 99%

Age-related changes of apoptotic cell death in human lymphocytes

Schindowski

Leutner

Müller

et al. 2000

Neurobiology of Aging

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Apoptosis seems to be involved in irnmunosenescence associated with aging. Moreover, in lymphocytes (PBL) of patients with Akheimer's disease, an increased susceptibirity to the apoprotic pathway has been described possibly due to impaired protection o f oxidative stress. Accordingly. it seemed to be of particular interest to investigate the contribution of normal aging to the susceptibility from human lymphocytes 20 programmed cell death. We coiild show that PBL from elderly individuals (>60 years) accumuIate apoptosing cells to a significant higher extent in spontaneous and activation-induced cell death compared to younger controls (<35 years). Treatment with the oxidative Stressor 2-deoxy-D-ribose or with agonistic-CD95-antibody pronounced this effect even more implicating a higher sensitivity to reactive oxygen species and a higher functionril CD95 expression, respectively. In addition, expression of the activation markerc HLA-DR and CD95 was significantly increased in CD3 "-cells of aged subjects, while expression of CD25 did not seem to be affected by age.Expression of Bcl-2 was increased in aging and comlated with the number o f apoptotic cells.Kqwordv. &in& Apoptosis: 1,yrnphocytes; Oxidativc stress; dctivation markers; Bcl-2 Programmed cell death (PCD) or apoptosis is of particular interest in aging, as it is thought X o play an irnportant role in various age-related degenerative diseases. Apoptosis of white bIood cells could be one reason for the decrease of the total number of leukocytes and the decrease of the immune response with aging related Z o Cancer, infections, and autoirnmune disorders [3]. Several changes in lymphocytes have been observed related to aging: diminished synthesis of g r o~h and survive factos 146,511, impaired intracellular calcium regulation [18], different surface malecule expression 1431, and defects of signal transdi~ction [36]. Some of these pathological changes are additionally altered in patients witl~ Alzheimer's disease (AD), but are not present in vascular dementia [13][14][15]171. In order to differentiate common and divergent mechanisms of an enhanced susceptibility of lymphocytes to apoptosis in aging and sporadic AD, we investigated in detail the molecular basis of enhanced apoptosis in aged human lymphocytes. Oxidative Stress increases with aging and ltads to enhanced cellular damage (e.g. Iipidperoxidation, protein oxidation, DNA damage (for review see ref.[IO]). In addition, reactive axygen species (ROS) can trigger cells to undergo pragrammed cell death and can act as second rnessenger by influencing transcription factors like NF-KB and AP-I. Increased oxidative stress and decreased ability to cope with ROS could ampliQ apoptotic cell death in aging lymphocytes. BcI-2 acts in an antioxidative and antiapoptotic way and can interfcre with the apoptotic pathway 17,471.One oF the best known and characterized surface receptors related to PCD in lymphocytes is ApollFas (CD95), a rnernber of the himor necrosis factor (W) superfamily. Stimulation of this recep...

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Section: Discussionmentioning

confidence: 99%

Age-related changes of apoptotic cell death in human lymphocytes

Schindowski

Leutner

Müller

et al. 2000

Neurobiology of Aging

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“…To discriminate A␤40 from A␤42 species we monitored intracellular as well as secreted A␤ terminating at amino acid 42 or amino acid 40 by using a previously established ELISA assay (12,22,23). To detect all species of A␤ generated, we specifically detected A␤ peptides beginning with Asp 1 (A␤1-40, A␤1-42) but also A␤ peptides beginning at alternative cleavage sites (A␤x-40, A␤x-42) which are abundant in kidney 293 cells and might play an important role during the disease (4 -11).…”

Section: Resultsmentioning

confidence: 99%

Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42

Wild-Bode¹,

Yamazaki²,

Capell³

et al. 1997

Journal of Biological Chemistry

300

212

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“…Apoptosis-The TUNEL assay was performed with a kit distributed by Oncor, as described previously (41,42). Briefly, F11 cells or COS-7 cells (ϳ4 ϫ 10 4 cells/well) were seeded onto glass coverslips with in a 24-well dish.…”

Section: Methodsmentioning

confidence: 99%

“…To evaluate this possibility, we employed an established assay system to detect apoptotic cell death (41,42). The caveolin-1 cDNA (pCB-7-Cav-1) or vector alone (pCB-7) were transiently expressed in F11 cells.…”

Section: Caveolin-1 Expression Inhibits Ras-mediated Transcriptional mentioning

confidence: 99%

“…The caveolin-1 cDNA (pCB-7-Cav-1) or vector alone (pCB-7) were transiently expressed in F11 cells. Nucleosomal DNA fragmentation in these cells was directly assessed by the TUNEL assay (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate (dUTP) nick-end labeling) (41,42). Fig.…”

Section: Caveolin-1 Expression Inhibits Ras-mediated Transcriptional mentioning

confidence: 99%

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Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-independent Growth

Engelman¹,

Wykoff²,

Yasuhara³

et al. 1997

Journal of Biological Chemistry

Self Cite

344

336

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Caveolae are plasma membrane-attached vesicular organelles. Caveolin-1, a 21-24-kDa integral membrane protein, is a principal component of caveolae membranes in vivo. Both caveolae and caveolin are most abundantly expressed in terminally differentiated cells: adipocytes, endothelial cells, and muscle cells. Conversely, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes such as v-abl and H-ras (G12V); caveolae are absent from these cell lines. However, its remains unknown whether down-regulation of caveolin-1 protein and caveolae organelles contributes to their transformed phenotype.Here, we have expressed caveolin-1 in oncogenically transformed cells under the control of an inducible-expression system. Regulated induction of caveolin-1 expression was monitored by Western blot analysis and immunofluorescence microscopy. Our results indicate that caveolin-1 protein is expressed well using this system and correctly localizes to the plasma membrane. Induction of caveolin-1 expression in v-Abl-transformed and H-Ras (G12V)-transformed NIH 3T3 cells abrogated the anchorage-independent growth of these cells in soft agar and resulted in the de novo formation of caveolae as seen by transmission electron microscopy. Consistent with its antagonism of Ras-mediated cell transformation, caveolin-1 expression dramatically inhibited both Ras/MAPK-mediated and basal transcriptional activation of a mitogen-sensitive promoter. Using an established system to detect apoptotic cell death, it appears that the effects of caveolin-1 may, in part, be attributed to its ability to initiate apoptosis in rapidly dividing cells. In addition, we find that caveolin-1 expression levels are reversibly down-regulated by two distinct oncogenic stimuli. Taken together, our results indicate that down-regulation of caveolin-1 expression and caveolae organelles may be critical to maintaining the transformed phenotype in certain cell populations.

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G Protein-Mediated Neuronal DNA Fragmentation Induced by Familial Alzheimer's Disease-Associated Mutants of APP

Cited by 217 publications

References 39 publications

Age-related changes of apoptotic cell death in human lymphocytes

Age-related changes of apoptotic cell death in human lymphocytes

Intracellular Generation and Accumulation of Amyloid β-Peptide Terminating at Amino Acid 42

Recombinant Expression of Caveolin-1 in Oncogenically Transformed Cells Abrogates Anchorage-independent Growth

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