Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715→Met βAPP-770 mutation responsible for probable early-onset Alzheimer's disease

We have identified a novel beta amyloid precursor protein (beta APP) mutation (V715M-beta APP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked beta APP mutations reported to date, overexpression of V715M-beta APP in human HEK293 cells and murine neurons reduces total A beta production and increases the recovery of the physiologically secreted product, APP alpha. V715M-beta APP significantly reduces A beta 40 secretion without affecting A beta 42 production in HEK293 cells, However, a marked increase in N-terminally truncated A beta ending at position 42 (x-42A beta) is observed, whereas its counterpart x-40A beta is not affected. These results suggest that, in some eases, familial A beta may be associated with a reduction in the overall production of A beta but may be caused by increased production of truncated forms of A beta ending at the 42 position.