Increased expression of the oligopeptidase THOP1 is a neuroprotective response to Abeta toxicity.
In a comprehensive proteomics study aiming at the identification of proteins associated with amyloid-beta (Abeta)-mediated toxicity in cultured cortical neurons, we have identified Thimet oligopeptidase (THOP1). Functional modulation of THOP1 levels in primary cortical neurons demonstrated that its overexpression was neuroprotective against Abeta toxicity, while RNAi knockdown made neurons more vulnerable to amyloid peptide. In the TgCRND8 transgenic mouse model of amyloid plaque deposition, an age-dependent increase of THOP1 expression was found in brain tissue, where it co-localized with Abeta plaques. In accordance with these findings, THOP1 expression was significantly increased in human AD brain tissue as compared to non-demented controls. These results provide compelling evidence for a neuroprotective role of THOP1 against toxic effects of Abeta in the early stages of AD pathology, and suggest that the observed increase in THOP1 expression might be part of a compensatory defense mechanism of the brain against an increased Abeta load.
Siena Biotech SpA, Discovery Research, Via Fiorentina 1, 53100 Siena, Italy.
Giuseppe
G
Pollio
Jeroen J M
JJ
Hoozemans
Claus A
CA
Andersen
Renza
R
Roncarati
Maria Cristina
MC
Rosi
Elise S
ES
van Haastert
Tamara
T
Seredenina
Daniela
D
Diamanti
Stefano
S
Gotta
Anna
A
Fiorentini
Letizia
L
Magnoni
Roberto
R
Raggiaschi
Annemieke J M
AJ
Rozemuller
Fiorella
F
Casamenti
Andrea
A
Caricasole
Georg C
GC
Terstappen
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008875:Middle Aged; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D016229:Amyloid beta-Peptides; D034741:RNA, Small Interfering; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase