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Article type: Research Article
Authors: Owens, Laurena; 1 | Bracewell, Joshuaa; 1 | Benedetto, Alexandrea | Dawson, Neila | Gaffney, Christopherb | Parkin, Edwarda; *
Affiliations: [a] Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom | [b] Lancaster Medical School, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom
Correspondence: [*] Correspondence to: Edward Parkin, Division of Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster, United Kingdom. Tel.: +44 1524 592246; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: 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. Methods:AβPP proteolysis was characterized by immunoblotting in mock-, wild-type AβPP (wtAβPP)-, BACE1-, and Swedish mutant AβPP (SweAβPP)-transfected cells. AβPP beta prime cleavage was confirmed through secretase inhibitor studies and C-terminal fragment analysis. The roles of sAβPPα and sAβPPβ’ in cell viability were confirmed by overexpression studies. Results:Despite producing enhanced Aβ peptide levels, wtAβPP- and SweAβPP-transfected cells did not exhibit reduced viability whereas BACE1-transfected cells did. sAβPPα generation in SH-SY5Y-BACE1 cells was virtually ablated in lieu of BACE1-mediated sAβPPβ’ production. sAβPPα overexpression in SH-SY5Y-BACE1 cells restored viability whereas sAβPPβ’ overexpression decreased viability further. The anti-AβPP 6E10 antibody was shown to cross-react with sAβPPβ’. Conclusion:sAβPPα depletion and/or sAβPPβ’ accumulation, but not elevated Aβ peptide levels, represent the cytotoxic mechanism following BACE1 overexpression in SH-SY5Y cells. These data support the novel concept that competitive sAβPPα depletion by BACE1 beta prime activity might contribute to AD. The cross-reactivity of 6E10 with AβPPβ’also questions whether previous studies assessing sAβPPα as a biomarker using this antibody should be revisited.
Keywords: Alpha-secretase, Alzheimer’s disease, amyloid-beta protein precursor, beta-secretase, beta prime
DOI: 10.3233/JAD-215457
Journal: Journal of Alzheimer's Disease, vol. 86, no. 3, pp. 1201-1220, 2022
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