Up-regulation of glycohydrolases in Alzheimer's Disease fibroblasts correlates with Ras activation.
The lysosomal system is up-regulated in the brain of patients with Alzheimer's Disease (AD), as demonstrated by previous experiments carried out in postmortem samples of brain patients. In this paper we provide evidence that an up-regulation of lysosomal glycohydrolases (alpha-D-mannosidase, beta-D-hexosaminidase, and beta-D-galactosidase) takes place in skin fibroblasts from AD patients affected either by sporadic or familial forms and is detectable also in presymptomatic subjects carrying the above mutations but healthy at the time of skin biopsy. This increase of enzyme activity is consequent to a transcriptional up-regulation. The oncogene Ras appears to be involved in the regulation of enzymatic activity. A parallel increase of Ras transcript and Ras protein, without an increase of p44/p42 MAPK activation was revealed in the same AD fibroblasts. An activation of p38 MAPK already described to occur in neurodegenerative diseases such as Alzheimer's, was also found in fibroblasts derived from AD patients. High levels of expression of the constitutively active form of Ras in normal or AD fibroblasts induced glycohydrolases up-regulation. Overall results demonstrated that glycohydrolases up-regulation, as well as Ras up-regulation, are early markers of AD, detectable at peripheral level, and good candidates to be exploited for diagnostic purposes. These data also provide the first proof for a role of Ras in regulating lysosomal glycohydrolases expression.
Emiliani
Carla
C
Dipartimento di Scienze Biochimiche e Biotecnologie Molecolari, Università degli Studi di Perugia, via del Giochetto, 06122 Perugia, Italy.
Urbanelli
Lorena
L
Racanicchi
Leda
L
Orlacchio
Antonio
A
Pelicci
Giuliana
G
Sorbi
Sandro
S
Bernardi
Giorgio
G
Orlacchio
Aldo
A
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008361:Mannosidases / Q000378:metabolism; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D043323:alpha-Mannosidase; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism*
D012313:RNA; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D006026:Glycoside Hydrolases; D008361:Mannosidases; D043323:alpha-Mannosidase; D018631:ras Proteins