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.
Pollio
Giuseppe
G
Siena Biotech SpA, Discovery Research, Via Fiorentina 1, 53100 Siena, Italy.
Hoozemans
Jeroen J M
JJ
Andersen
Claus A
CA
Roncarati
Renza
R
Rosi
Maria Cristina
MC
van Haastert
Elise S
ES
Seredenina
Tamara
T
Diamanti
Daniela
D
Gotta
Stefano
S
Fiorentini
Anna
A
Magnoni
Letizia
L
Raggiaschi
Roberto
R
Rozemuller
Annemieke J M
AJ
Casamenti
Fiorella
F
Caricasole
Andrea
A
Terstappen
Georg C
GC
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