Novel T719P AβPP Mutation Unbalances the Relative Proportion of Amyloid-β Peptides

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