BACE1 Overexpression Reduces SH-SY5Y Cell Viability Through a Mechanism Distinct from Amyloid-β Peptide Accumulation: Beta Prime-Mediated Competitive Depletion of sAβPPα.

Background: The Alzheimer's disease (AD)-associated amyloid-beta protein precursor (AβPP) can be cleaved by β-site AβPP cleaving enzyme 1 (BACE1) and the γ-secretase complex to yield neurotoxic amyloid-β (Aβ) peptides. However, AβPP can also be cleaved in a 'non-amyloidogenic' manner either by α-secretase to produce soluble AβPP alpha (sAβPPα) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated 'beta prime' activity yielding soluble AβPP beta prime (sAβPPβ').

Objective: To determine whether sAβPPα depletion, as opposed to Aβ peptide accumulation, contributes to cytotoxicity in AD-relevant SH-SY5Y neuroblastoma cell models.