Novel T719P AbetaPP mutation unbalances the relative proportion of amyloid-beta peptides.
A novel missense mutation (T719P) in the amyloid-beta protein precursor (AbetaPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer's disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-beta peptides (Abeta) in cerebrospinal fluid (CSF) of the AbetaPP mutated patient, healthy control subjects (n = 10), and of two subjects carrying mutations in presenilins genes (PS) (i.e., PS1 P117L and PS2 T122R): seven different C-terminally and three N-terminally truncated Abeta peptides were found in CSF. The investigated AbetaPP as well as PS mutations were associated with an overall reduction of Abeta species, except for Abeta(10-40). Interestingly, the AbetaPP T719P mutation unbalanced the relative proportion of Abeta peptides with a reduction of Abeta(1-40) and Abeta(1-42) paralleled by an increase of Abeta(1-38) and Abeta(10-40). Despite the specific neuropeptidomic phenotype associated with the AbetaPP T719P mutation, the enrichment in Abeta(10-40) paralleled by depletion of Abeta(1-42) seems to be a common theme in familial AD. The AbetaPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AbetaPP epsilon-cleavage site.
Ghidoni
Roberta
R
Proteomics Unit, IRCCS Centro S. Giovanni di Dio-FBF, Brescia, Italy. rghidoni@fatebenefratelli.it
Albertini
Valentina
V
Squitti
Rosanna
R
Paterlini
Anna
A
Bruno
Anna
A
Bernardini
Silvia
S
Cassetta
Emanuele
E
Rossini
Paolo Maria
PM
Squitieri
Ferdinando
F
Benussi
Luisa
L
Binetti
Giuliano
G
D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010446:Peptide Fragments / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013912:Threonine / Q000235:genetics*; D014443:Tyrosine / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D013912:Threonine; D014443:Tyrosine