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

Abstract

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.