Release of excess amyloid β protein from a mutant amyloid β protein precursor

The 4-kilodalton amyloid β protein (Aβ), which forms fibrillar deposits in Alzheimer's disease (AD), is derived from a large protein referred to as the amyloid β protein precursor (βAPP). Human neuroblastoma (M17) cells transfected with constructs expressing wild-type βAPP or a mutant, βAPP_σNL, recently linked to familial AD were compared. After continuous metabolic labeling for 8 hours, cells expressing βAPP_ΔNL had five times more of an Aβ-bearing, carboxyl terminal, βAPP derivative than cells expressing wild-type βAPP and they released six times more Aβ into the medium. Thus this mutant βAPP may cause AD because its processing is altered in a way that releases increased amounts of Aβ.