Cerebrospinal fluid-induced retardation of amyloid beta aggregation correlates with Alzheimer's disease and the APOE epsilon 4 allele

• Misfolding and aggregation of amyloid beta (A beta) are key features of Alzheimer's disease (AD) pathogenesis, but the molecular events controlling this process are not known in detail. In vivo, A beta 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 A beta aggregation kinetics in relation to AD diagnosis and carrier status of the apolipoprotein E (APOE) epsilon 4 allele, the main genetic risk factor for sporadic AD. The aggregation of A beta was inhibited in the presence of CSF and, surprisingly, the effect was more pronounced in APOE epsilon 4 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 epsilon 4 functions in AD pathogenesis. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Keyword

Apolipoprotein epsilon 4

High density lipoproteins

Amyloid-beta

Aggregation

Thioflavin T

Neurofibrillary tangles

Kinetics

Inhibition

Cholesterol

apolipoprotein-e

density-lipoprotein

type-4 allele

in-vitro

protein

association

peptide

binding

subpopulations

purification

Neurosciences & Neurology

Publication and Content Type

ref (subject category)

art (subject category)