Differential post-translational modifications of transthyretin in Alzheimer's disease: a study of the cerebral spinal fluid.
Transthyretin (TTR) is a 55 kDa homotetrameric protein. TTR in the cerebral spinal fluid (CSF) is primarily synthesized by the choroid plexus. TTR can bind to the beta-amyloid peptide and a number of familial amyloidosis diseases (familial amyloid polyneuropathy) have been associated with its allele variants. In a transgenic mice model overexpression of TTR was positively correlated with a neuroprotective effect from the pathogenic APPsw mutation. TTR has a free reactive sulphydryl moiety located on the Cys(10) residue which has been implicated to undergo a variety of oxidation reactions. To examine the neuroprotective role of TTR, we investigated the conjugated forms of TTR with cysteine (Cys) and cysteinglycine (CsyGly) in the CSF of 39 probable Alzheimer's disease (AD)-affected subjects and in a cohort of subjects without cognitive impairment (27 subjects). Linear MALDI-TOF MS experiments were employed to obtain high-resolution protein profiling of TTR isoforms. Nano-LC-TANDEM MS combined with reflectron MALDI-TOF-MS was used to unequivocally assign the investigated TTR-conjugate signals. Our results indicate a differential distribution of TTR-Cys and TTR-CysGly adducts. Both oxidized forms of TTR are significantly less abundant in the AD group (p = 0.0001). The investigated population (66 subjects) was then diagnosed using the ratio of conjugated TTR to free TTR in each subject. A sensitivity >90% and a specificity >70% were derived from a receiver operating characteristic curve when the overall cohort is analysed by the TTR-Cys signals. This manuscript is the first report describing the presence of differential post-translational oxidations of TTR in the CSF of AD patients.
Biroccio
Antonino
A
Laboratori di Ricerca, Ospedale Pediatrico del Bambino Gesu'-IRCCS, Roma, Citta' del Vaticano.
Del Boccio
Piero
P
Panella
Marta
M
Bernardini
Sergio
S
Di Ilio
Carmine
C
Gambi
Domenico
D
Stanzione
Paolo
P
Sacchetta
Paolo
P
Bernardi
Giorgio
G
Martorana
Alessandro
A
Federici
Giorgio
G
Stefani
Alessandro
A
Urbani
Andrea
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D000595:Amino Acid Sequence; D015415:Biomarkers / Q000134:cerebrospinal fluid; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D011228:Prealbumin / Q000134:cerebrospinal fluid* / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013438:Sulfhydryl Compounds / Q000134:cerebrospinal fluid
D015415:Biomarkers; D011228:Prealbumin; D013438:Sulfhydryl Compounds