Interrelationship between the Levels of C9orf72 and Amyloid-β Protein Precursor and Amyloid-β in Human Cells and Brain Samples

Article type: Research Article

Authors: Leskelä, Stina^{a; 1} | Takalo, Mari^{a; b; 1} | Marttinen, Mikael^b | Huber, Nadine^a | Paananen, Jussi^b | Mitra, Vikram^h | Rauramaa, Tuomas^{c; e} | Mäkinen, Petra^b | Leinonen, Ville^g | Soininen, Hilkka^{d; f} | Pike, Ian^h | Remes, Anne M.^{d; f} | Hiltunen, Mikko^{b; d; f} | Haapasalo, Annakaisa^{a; f; *}

Affiliations: [a] A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland | [b] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [c] Institute of Clinical Medicine – Pathology, University of Eastern Finland, Kuopio, Finland | [d] Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland | [e] Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [f] NeuroCenter, Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland | [g] Neurosurgery of NeuroCenter, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland | [h] Proteome Sciences plc, Coveham House, Cobham, Surrey, UK

Correspondence: [*] Correspondence to: Annakaisa Haapasalo, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland (UEF), P. O. Box 1627 (Neulaniementie 2), 70211 Kuopio, Finland. Tel.: +358 40 355 2768; Fax: +358 17 163 025; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: A subset of C9orf72 repeat expansion-carrying frontotemporal dementia patients display an Alzheimer-like decrease in cerebrospinal fluid amyloid-β (Aβ) biomarker levels. We report that downregulation of C9orf72 in non-neuronal human cells overexpressing amyloid-β protein precursor (AβPP) resulted in increased levels of secreted AβPP fragments and Aβ, while levels of AβPP or its C-terminal fragments (CTFs) remained unchanged. In neuronal cells, AβPP and C83 CTF levels were decreased upon C9orf72 knockdown, but those of secreted AβPP fragments or Aβ remained unchanged. C9orf72 protein levels significantly increased in human brain with advancing neurofibrillary pathology and positively correlated with brain Aβ42 levels. Our data suggest that altered C9orf72 levels may lead to cell-type specific alterations in AβPP processing, but warrant further studies to clarify the underlying mechanisms.

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, C9orf72, frontotemporal dementia

DOI: 10.3233/JAD-170362

Journal: Journal of Alzheimer's Disease, vol. 62, no. 1, pp. 269-278, 2018