The possible place of cathepsins and cystatins in the puzzle of Alzheimer disease

Bernstein, Hans‐Gert; Kirschke, Heidrun; Wiederanders, Bernd; Pollak, Karl-Heinz; Zipress, Alexander; Rinne, Ari

doi:10.1007/bf02815106

Cited by 67 publications

(42 citation statements)

References 112 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The increase in lysosomes is likely an important finding, because abnormalities in lysosomes are considered a prominent morphologic marker of distressed neurons and because lysosomal abnormalities are associated with neurodegenerative diseases (20)(21)(22)(23)(24). Studies have suggested that accumulation of abnormal proteins, as in prion encephalopathies and formation of ␤͞A4 protein from its precursor in Alzheimer's disease, takes place in lysosome-related organelles (24).…”

Section: Atm؊͞؊ Mice Have Increased Numbers Of Lysosomes In Pcs Detecmentioning

confidence: 99%

ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation

Barlow

Ribaut‐Barassin

Zwingman

et al. 2000

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

164

103

View full text Add to dashboard Cite

We previously generated a mouse model with a mutation in the murine Atm gene that recapitulates many aspects of the childhood neurodegenerative disease ataxia-telangiectasia. Atm-deficient (Atm؊͞؊) mice show neurological defects detected by motor function tests including the rota-rod, open-field tests and hindpaw footprint analysis. However, no gross histological abnormalities have been observed consistently in the cerebellum of any line of Atm؊͞؊ mice analyzed in most laboratories. Therefore, it may be that the neurologic dysfunction found in these animals is associated with predegenerative lesions. We performed a detailed analysis of the cerebellar morphology in two independently generated lines of Atm؊͞؊ mice to determine whether there was evidence of neuronal abnormality. We found a significant increase in the number of lysosomes in Atm؊͞؊ mice in the absence of any detectable signs of neuronal degeneration or other ultrastructural anomalies. In addition, we found that the ATM protein is predominantly cytoplasmic in Purkinje cells and other neurons, in contrast to the nuclear localization of ATM protein observed in cultured cells. The cytoplasmic localization of ATM in Purkinje cells is similar to that found in human cerebellum. These findings suggest that ATM may be important as a cytoplasmic protein in neurons and that its absence leads to abnormalities of cytoplasmic organelles reflected as an increase in lysosomal numbers.

show abstract

Section: Atm؊͞؊ Mice Have Increased Numbers Of Lysosomes In Pcs Detecmentioning

confidence: 99%

ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation

Barlow

Ribaut‐Barassin

Zwingman

et al. 2000

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

164

103

View full text Add to dashboard Cite

show abstract

“…More specific functions have recently been postulated in a wide range of physiological and pathological processes. These include antigen presentation (3), prohormone processing (4), turnover of ␤-amyloid in Alzheimer's disease (5), tumor invasion (6), tumor angiogenesis (7), and apoptosis (8,9). …”

mentioning

confidence: 99%

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Felbor

Kessler²,

Mothes³

et al. 2002

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

308

217

View full text Add to dashboard Cite

Cathepsins B and L are widely expressed cysteine proteases implicated in both intracellular proteolysis and extracellular matrix remodeling. However, specific roles remain to be validated in vivo. Here we show that combined deficiency of cathepsins B and L in mice is lethal during the second to fourth week of life. Cathepsin B ؊/؊ ͞L ؊/؊ mice reveal a degree of brain atrophy not previously seen in mice. This is because of massive apoptosis of select neurons in the cerebral cortex and the cerebellar Purkinje and granule cell layers. Neurodegeneration is accompanied by pronounced reactive astrocytosis and is preceded by an accumulation of ultrastructurally and biochemically unique lysosomal bodies in large cortical neurons and by axonal enlargements. Our data demonstrate a pivotal role for cathepsins B and L in maintenance of the central nervous system.

show abstract

“…The enzyme was mainly found in the lysosomes of normal tissues and participates in intralysosomal turnover of cellular proteins and molecules assimilated from the extracellular environment as well as in the degradation of extracellular matrix components, prohormone processing (Shinagawa et al, 1990), and turnover of ␤-amyloids in Alzheimer's disease (Bernstein et al, 1996). Further functions of cathepsin B have been found with the development of cathepsin B-deficient mice.…”

mentioning

confidence: 99%

Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

Bien

Grätz²,

Sperker³

et al. 2004

Molecular Pharmacology

View full text Add to dashboard Cite

Anthracyclines such as doxorubicin remain among the most effective agents for the treatment of solid tumors and hematological malignancies. To overcome dose-limiting side effects like cardiotoxicity, an intensive effort has been undertaken to develop promising doxorubicin prodrugs that are specifically activated at the tumor site. One approach is the application of peptide prodrugs of doxorubicin. The enzyme cathepsin B catalyzes the activation of these prodrugs, and hence, the regulation of cathepsin B by antitumor agents could influence the efficacy of peptide prodrugs using this protease. In the present investigation, the effects of doxorubicin on cathepsin B expression in the human cervix carcinoma cell line HeLa were examined. Exposure to doxorubicin induced a time-and dose-dependent up-regulation of cathepsin B expression on mRNA, protein, and activity levels. In the cathepsin B gene promoter region, a potential nuclear factor B (NF-B) binding site could be identified. Pretreatment of HeLa cells with specific NF-B inhibitors abrogated the induction of cathepsin B expression. Doxorubicin-induced degradation of the inhibitory protein IB could be prevented by pretreatment with a specific proteasome inhibitor, resulting in a significant reduction of the doxorubicininduced cathepsin B expression. Finally, binding of NF-B subunits p50 and p65 to the NF-B binding site in the cathepsin B gene promoter region could be demonstrated by electrophoretic mobility shift assay. In summary, our data clearly indicate that doxorubicin induces cathepsin B expression and activity via NF-B. These findings contribute to a better understanding of tumor targeting with peptide prodrugs and help to define a possible mechanism of doxorubicin toxicity in tumor cells.

show abstract

The possible place of cathepsins and cystatins in the puzzle of Alzheimer disease

Cited by 67 publications

References 112 publications

ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation

ATM is a cytoplasmic protein in mouse brain required to prevent lysosomal accumulation

Neuronal loss and brain atrophy in mice lacking cathepsins B and L

Nuclear Factor-κB Mediates Up-Regulation of Cathepsin B by Doxorubicin in Tumor Cells

Contact Info

Product

Resources

About