BACE-2 is overexpressed in Down's syndrome.
Brain deposition of the amyloid-beta protein (Abeta) is a frequent complication of Down's syndrome (DS) patients. Abeta peptide is generated by endoproteolytic processing of Abeta precursor protein by gamma and beta secretases. Recently a transmembrane aspartyl protease, BACE, has been identified as the beta-secretase, and its homologous BACE-2 has also been described. BACE-2 gene resides on chromosome 21 in the obligate DS region. It cleaves Abeta precursor protein at its beta site and more efficiently at a different site within Abeta. In the present study we characterized the BACE-2 gene and protein expression in the DS patients and healthy control. We analyzed, by using a nonradioactive ribonuclease protection assay, the levels of BACE-2 mRNA expression in primary skin fibroblasts. The analysis revealed a 2.6-fold increase in BACE-2 mRNA levels in the DS group compared to the levels observed in the control group. Western blot analysis revealed no difference between DS and control in BACE-2 protein levels in the intracellular compartment. In the medium conditioned by fibroblast, we revealed an evident secretion of BACE-2 protein, represented by two different molecular weights, remarkably increased in DS fibroblasts. BACE-2 overexpression was also confirmed in the DS fetal brains and human neural embryonic DS stem cells in which conditioned media BACE-2 was secreted. These data highlight the importance of the extracellular compartment where BACE-2 overexpression could play a role in plaque formation in DS patients.
Barbiero
L
L
Neurobiology Laboratory, Memory Clinic, IRCCS Centro S. Giovanni di Dio-FbF, Brescia, Italy.
Benussi
L
L
Ghidoni
R
R
Alberici
A
A
Russo
C
C
Schettini
G
G
Pagano
S F
SF
Parati
E A
EA
Mazzoli
F
F
Nicosia
F
F
Signorini
S
S
Feudatari
E
E
Binetti
G
G
D000328:Adult; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000201:enzymology*; D001923:Brain Chemistry; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry; D004314:Down Syndrome / Q000201:enzymology*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D008970:Molecular Weight; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D012016:Reference Values; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism
D017077:Culture Media, Conditioned; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases