Advanced

Cerebrospinal fluid-induced retardation of amyloid β aggregation correlates with Alzheimer's disease and the APOE ε4 allele

Padayachee, E. R.; Zetterberg, H. LU ; Portelius, E.; Borén, J.; Molinuevo, J. L.; Andreasen, N.; Cukalevski, R. LU ; Linse, S. LU ; Blennow, K. and Andreasson, U. (2016) In Brain Research 1651. p.11-16
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Aggregation, Amyloid-β, Apolipoprotein ε4, Cholesterol, High density lipoproteins, Inhibition, Kinetics, Neurofibrillary tangles, Thioflavin T
in
Brain Research
volume
1651
pages
6 pages
publisher
Elsevier
external identifiers
  • scopus:84991100113
  • wos:000387527100002
ISSN
0006-8993
DOI
10.1016/j.brainres.2016.09.022
language
English
LU publication?
yes
id
ae7160bd-653e-4cfc-b525-d281da4920c6
date added to LUP
2016-10-28 08:55:08
date last changed
2017-10-22 05:21:07
@article{ae7160bd-653e-4cfc-b525-d281da4920c6,
  abstract     = {<p>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.</p>},
  author       = {Padayachee, E. R. and Zetterberg, H. and Portelius, E. and Borén, J. and Molinuevo, J. L. and Andreasen, N. and Cukalevski, R. and Linse, S. and Blennow, K. and Andreasson, U.},
  issn         = {0006-8993},
  keyword      = {Aggregation,Amyloid-β,Apolipoprotein ε4,Cholesterol,High density lipoproteins,Inhibition,Kinetics,Neurofibrillary tangles,Thioflavin T},
  language     = {eng},
  month        = {11},
  pages        = {11--16},
  publisher    = {Elsevier},
  series       = {Brain Research},
  title        = {Cerebrospinal fluid-induced retardation of amyloid β aggregation correlates with Alzheimer's disease and the APOE ε4 allele},
  url          = {http://dx.doi.org/10.1016/j.brainres.2016.09.022},
  volume       = {1651},
  year         = {2016},
}