γ-secretase processing of APLP1 leads to the production of a p3-like peptide that does not aggregate and is not toxic to neurons

The amyloid precursor-like protein-1 (APLP1) is a member of a protein family that includes the Alzheimer's disease-associated amyloid precursor protein (APP). While much is known about the proteolytic processing of APP, fewer details are available about APLP1. Using Chinese hamster ovarian cells stably transfected with human APLP1 and a novel juxtamembrane anti-APLP1 antibody, we demonstrate the detection of a secreted ∼ 3.5 kDa APLP1-derived peptide (ALP-1). The production of this peptide is abolished by inhibition of γ-secretase, but not β-secretase, suggesting that ALP-1 is analogous to the p3 fragment produced from APP. However, unlike p3 or Aβ, ALP-1 shows no obvious propensity for aggregation and is not toxic to neuronal cells. Moreover, using two distinct experimental paradigms, we demonstrate that neither cell-derived nor chemically synthesized ALP-1 influences the oligomerization or aggregation of Aβ.