The Expression of Transthyretin and Amyloid-β Protein Precursor is Altered in the Brain of Idiopathic Normal Pressure Hydrocephalus Patients

Article type: Research Article

Authors: Laiterä, Tiina^{a; b} | Kurki, Mitja I.^b | Pursiheimo, Juha-Pekka^c | Zetterberg, Henrik^d | Helisalmi, Seppo^a | Rauramaa, Tuomas^{e; f} | Alafuzoff, Irina^g | Remes, Anne M.^a | Soininen, Hilkka^a | Haapasalo, Annakaisa^{a; i} | Jääskeläinen, Juha E.^b | Hiltunen, Mikko^{a; h; 1} | Leinonen, Ville^{b; 1; *}

Affiliations: [a] Institute of Clinical Medicine – Neurology, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, Kuopio, Finland | [b] Institute of Clinical Medicine – Neurosurgery, University of Eastern Finland and Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland | [c] Institute of Biomedicine, University of Turku, Turku, Finland | [d] Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden | [e] Institute of Clinical Medicine - Pathology, University of Eastern Finland and Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [f] Department of Pathology, Kuopio University Hospital, Kuopio, Finland | [g] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden | [h] Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland | [i] Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, Kuopio, Finland

Correspondence: [*] Correspondence to: Ville Leinonen, MD, PhD, Department of Neurosurgery, Kuopio University Hospital, P. O. Box 100, FI-70029 KYS, Finland. Tel.: +358 44 717 2303; Fax: +358 17 173 916; E-mail: [email protected]

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

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is a dementing condition in which Alzheimer’s disease (AD)-related amyloid-β (Aβ) plaques are frequently observed in the neocortex. iNPH patients with prominent Aβ pathology show AD-related alterations in amyloid-β protein precursor (AβPP) processing resulting from increased γ-secretase activity. Objectives: Our goal was to assess potential alterations in the global gene expression profile in the brain of iNPH patients as compared to non-demented controls and to evaluate the levels of the identified targets in the cerebrospinal fluid (CSF) of iNPH patients. Methods: The genome-wide expression profile of ∼35,000 probes was assessed in the RNA samples obtained from 22 iNPH patients and eight non-demented control subjects using a microarray chip. The soluble levels of sAβPPα, sAβPPβ, and transthyretin (TTR) were measured from the CSF of 102 iNPH patients using ELISA. Results: After correcting the results for multiple testing, significant differences in the expression of TTR and A βPP were observed between iNPH and control subjects. The mRNA levels of TTR were on average 17-fold lower in iNPH samples compared to control samples. Conversely, the expression level of A βPP was on average three times higher in iNPH samples as compared to control samples. Interestingly, the expression of α-secretase (ADAM10) was also increased in iNPH patients. In the lumbar CSF samples, soluble TTR levels showed a significant positive correlation with sAβPPα and sAβPPβ, but TTR levels did not predict the brain pathology or the shunt response. Conclusions: These findings suggest differences in the expression profile of key factors involved in AD-related cellular events in the brain of iNPH patients.

Keywords: Alzheimer’s disease, amyloid-β protein precursor, gene expression profiling, idiopathic normal pressure hydrocephalus, transthyretin

DOI: 10.3233/JAD-150268

Journal: Journal of Alzheimer's Disease, vol. 48, no. 4, pp. 959-968, 2015