Increased PCSK9 Cerebrospinal Fluid Concentrations in Alzheimer's Disease.
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.



We compared PCSK9 levels in CSF of AD patients and non-AD controls and looked at correlations with CSF total apoE and apoE4.



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.



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).



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.
Department of Pharmacy, University of Parma, Parma, Italy.
Francesca
F
Zimetti
Department of Neurosciences, University of Parma, Parma, Italy.|Centre for Cognitive Disorders and Dementia (CDCD), AUSL, Parma, Italy.
Paolo
P
Caffarra
Department of Pharmacy, University of Parma, Parma, Italy.
Nicoletta
N
Ronda
Department of Pharmacy, University of Parma, Parma, Italy.
Elda
E
Favari
Department of Pharmacy, University of Parma, Parma, Italy.
Maria Pia
MP
Adorni
Department of Pharmacy, University of Parma, Parma, Italy.
Ilaria
I
Zanotti
Department of Pharmacy, University of Parma, Parma, Italy.
Franco
F
Bernini
Department of Neurosciences, University of Parma, Parma, Italy.
Federica
F
Barocco
Department of Neurosciences, University of Parma, Parma, Italy.
Marco
M
Spallazzi
Neurology Unit, Department of Pathophysiology and Transplantation, University of Milano, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milano, Italy.
Daniela
D
Galimberti
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Chiara
C
Ricci
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
Massimiliano
M
Ruscica
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.|Multimedica IRCCS, Milano, Italy.
Alberto
A
Corsini
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Padova, Italy.
Nicola
N
Ferri
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D000073216:Mental Status and Dementia Tests; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D000071449:Proprotein Convertase 9 / Q000134:cerebrospinal fluid*; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
Alzheimer’s disease; apolipoprotein E4; cerebrospinal fluid; cholesterol; human; proprotein convertase subtilisin kexin 9