Novel T719P AβPP mutation unbalances the relative proportion of amyloid-β peptides

A novel missense mutation (T719P) in the amyloid-β protein precursor (AβPP) 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-β peptides (Aβ) in cerebrospinal fluid (CSF) of the AβPP 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 Aβ peptides were found in CSF. The investigated AβPP as well as PS mutations were associated with an overall reduction of Aβ species, except for Aβ-{10-40}. Interestingly, the AβPP T719P mutation unbalanced the relative proportion of Aβ peptides with a reduction of Aβ-{1-40} and Aβ-{1-42} paralleled by an increase of Aβ-{1-38} and Aβ-{10-40}. Despite the specific neuropeptidomic phenotype associated with the AβPP T719P mutation, the enrichment in Aβ-{10-40} paralleled by depletion of Aβ-{1-42} seems to be a common theme in familial AD. The AβPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AβPP ε-cleavage site.