Cathepsin D expression is decreased in Alzheimer's disease fibroblasts.
Cathepsin D (CTSD), a protease detectable in different cell types whose primary function is to degrade proteins by bulk proteolysis in lysosomes, has been suggested to be involved in Alzheimer's disease (AD). In fact, there is increasing evidence that disturbance of the normal balance and localization of cathepsins may contribute to neurodegeneration in AD [Nakanishi H. Neuronal and microglial cathepsins in aging and age-related diseases. Aging Res Rev 2003; 2(4):367-81]. Here, we provide evidence of an altered balance of CTSD in skin fibroblasts from patients affected either by sporadic or familial forms of AD. In particular, we demonstrate that CTSD is down regulated at both transcriptional and translational level and its processing is altered in AD fibroblasts. The oncogene Ras is involved in the regulation of CTSD, as high expression level of the constitutively active form of Ras in normal or AD fibroblasts induces CTSD down-regulation. p38 MAPK signalling pathway also appears to down-modulate CTSD level. Overall results reinforce the hypothesis that a lysosomal impairment may be involved in AD pathogenesis and can be detected not only in the CNS but also at a peripheral level.
Urbanelli
Lorena
L
Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università di Perugia, Via del Giochetto, Perugia 06126, Italy.
Emiliani
Carla
C
Massini
Carlo
C
Persichetti
Emanuele
E
Orlacchio
Antonio
A
Pelicci
Giuliana
G
Sorbi
Sandro
S
Hasilik
Andrej
A
Bernardi
Giorgio
G
Orlacchio
Aldo
A
D000328:Adult; D000544:Alzheimer Disease / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D018631:ras Proteins / Q000502:physiology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D048051:p38 Mitogen-Activated Protein Kinases; D002402:Cathepsin D; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one