title: Cerebrospinal fluid-induced retardation of amyloid β aggregation correlates with Alzheimer's disease and the APOE ε4 allele.
abstract: Misfolding and aggregation of amyloid β (Aβ) are key features of Alzheimer's disease (AD) pathogenesis, but the molecular events controlling this process are not known in detail. In vivo, Aβ aggregation and plaque formation occur in the interstitial fluid of the brain extracellular matrix. This fluid communicates freely with cerebrospinal fluid (CSF). Here, we examined the effect of human CSF on Aβ aggregation kinetics in relation to AD diagnosis and carrier status of the apolipoprotein E (APOE) ε4 allele, the main genetic risk factor for sporadic AD. The aggregation of Aβ was inhibited in the presence of CSF and, surprisingly, the effect was more pronounced in APOE ε4 carriers. However, by fractionation of CSF using size exclusion chromatography, it became evident that it was not the ApoE protein itself that conveyed the inhibition, since the retarding species eluted at lower volume, corresponding to a much higher molecular weight, than ApoE monomers. Cholesterol quantification and immunoblotting identified high-density lipoprotein particles in the retarding fractions, indicating that such particles may be responsible for the inhibition. These results add information to the yet unresolved puzzle on how the risk factor of APOE ε4 functions in AD pathogenesis.
authors.affiliation: Clinical Neurochemistry Lab, Inst. of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. Electronic address: padayachee.eden@gmail.com.
authors.forename: E R
authors.initials: ER
authors.lastname: Padayachee
authors.affiliation: Clinical Neurochemistry Lab, Inst. of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, United Kingdom.
authors.forename: H
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: Clinical Neurochemistry Lab, Inst. of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Portelius
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Borén
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari and Pasqual Maragall Foundation, Barcelona, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Department of Geriatrics, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Andreasen
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden.
authors.forename: R
authors.initials: R
authors.lastname: Cukalevski
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Linse
authors.affiliation: Clinical Neurochemistry Lab, Inst. of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
authors.forename: K
authors.initials: K
authors.lastname: Blennow
authors.affiliation: Clinical Neurochemistry Lab, Inst. of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Andreasson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D052160:Benzothiazoles; D016022:Case-Control Studies; D002555:Cerebrospinal Fluid / Q000737:chemistry*; D008076:Cholesterol, HDL / Q000134:cerebrospinal fluid / Q000378:metabolism; D002850:Chromatography, Gel; D005260:Female; D006579:Heterozygote; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000737:chemistry*; D011446:Prospective Studies; D055503:Protein Multimerization; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D052160:Benzothiazoles; D008076:Cholesterol, HDL; D010446:Peptide Fragments; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T
keywords: Aggregation; Amyloid-β; Apolipoprotein ε4; Cholesterol; High density lipoproteins; Inhibition; Kinetics; Neurofibrillary tangles; Thioflavin T