Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer’s Disease

Article type: Research Article

Authors: Zimetti, Francesca^a | Caffarra, Paolo^{b; c} | Ronda, Nicoletta^a | Favari, Elda^a | Adorni, Maria Pia^a | Zanotti, Ilaria^a | Bernini, Franco^{a; *} | Barocco, Federica^b | Spallazzi, Marco^b | Galimberti, Daniela^d | Ricci, Chiara^e | Ruscica, Massimiliano^e | Corsini, Alberto^{e; f} | Ferri, Nicola^g

Affiliations: [a] Department of Pharmacy, University of Parma, Parma, Italy | [b] Department of Neurosciences, University of Parma, Parma, Italy | [c] Centre for Cognitive Disorders and Dementia (CDCD), AUSL, Parma, Italy | [d] Neurology Unit, Department of Pathophysiology and Transplantation, University of Milano, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milano, Italy | [e] Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy | [f] Multimedica IRCCS, Milano, Italy | [g] Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy

Correspondence: [*] Correspondence to: Professor Franco Bernini, Department of Pharmacy, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy. Tel.: +39 0521 905039; Fax: +39 0521 905040; E-mail: [email protected].

Abstract: Background: Alzheimer’s disease (AD) has been associated with dysregulation of brain cholesterol trafficking and abnormal production of apolipoprotein E isoform 4 (apoE4). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein present in serum and cerebrospinal fluid (CSF) degrading the low-density lipoprotein receptor (LDLr) and other apoE-binding receptors involved in neuron cholesterol uptake. The role of PCSK9 in AD is controversial. Objective: We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4. Methods: CSF from AD (n = 30) and from age and sex-matched non-AD patients (n = 30) was collected by lumbar puncture for routine diagnosis. CSF PCSK9, total apoE, and apoE4 levels were measured by ELISA. AD patients showed the typical CSF neurobiomarker pattern (decreased Aβ42 and increased tau and phospho-tau) and impaired cognitive performances, as indicated by the scores of the Mini-Mental State Examination test. Results: PCSK9 levels in CSF were higher in AD than in non-AD subjects (+1.45 fold; p = 0.0049). CSF total apoE concentrations did not differ between the two groups, while apoE4 levels were higher in AD subjects (+3.34 fold; p = 0.0068). Considering all samples, a significant positive correlation was found between PCSK9 and apoE4 (r = 0.4409; p = 0.0006). PCSK9 levels were higher in APOE ɛ4 carriers, reaching statistical significance in the AD group (+1.45 fold; p = 0.0454). Conclusion: These results report for the first time an alteration of CSF PCSK9 levels in AD and suggest a pathophysiological link between PCSK9, apoE4, and AD.

Keywords: Alzheimer’s disease, apolipoprotein E4, cerebrospinal fluid, cholesterol, human, proprotein convertase subtilisin kexin 9

DOI: 10.3233/JAD-160411

Journal: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 315-320, 2017