Relative ratio and level of amyloid-β 42 surrogate in cerebrospinal fluid of familial Alzheimer disease patients with presenilin 1 mutations.

Background: Presenilin 1 (PS1) mutations associated with familial Alzheimer disease (FAD) generally increase the amyloid-beta 42 (A beta 42) to A beta 40 ratio secreted in cultured cells. Some of these mutants reduce the secretion of A beta 40 rather than increase that of A beta 42. Since it has been difficult to estimate A beta 42 secretion in brains of P51-FAD patients due to substantial A beta 42 accumulation, it remains unknown whether the enhanced A beta 42 to A beta 40 ratio in brains of FAD patients is caused by elevated 442 secretion or by reduced secretion of A beta 40. Objective/Methods: Cerebrospinal fluids (CSF) of PS1-FAD patients and neurological control patients (controls) were collected. Levels of CSF amyloid precursorlike protein-1-derived A beta-like peptide (APL1 beta), including APL1 beta 28, an A beta 42 surrogate marker, were quantified by liquid chromatography tandem mass spectrometry, and A beta 42 secretion in the brain was estimated. Results: The relative ratio of CSF APL1 beta 28 to total APL1 beta was higher in PS1-FAD patients than in controls. Importantly, CSF APL1 beta 28 was not significantly higher. However, C-terminally shorter CSF APL1 beta 25 and APL1 beta 27 were significantly lower in PS1-FAD patients and, as expected, so were CSF A beta 40 and A beta 42. Conclusion: A higher relative ratio of the CSF A beta 42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive A beta 42 accumulation in the PS1-FAD brain occurs without an apparent increase in A beta 42 secretion. (C) 2013 S. Karger AG, Basel