Loading…

Increased CSF-decorin predicts brain pathological changes driven by Alzheimer’s Aβ amyloidosis

Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer’s disease (AD) which is characterized by amyloid-β (Aβ) amyloidosis. Here, we used two App knock-in mouse models, App NL-F/NL-F and App NL-G-F/NL-G-F , exhibiting AD-like Aβ pathology to analyze how the brain patholo...

Full description

Saved in:
Bibliographic Details
Published in:Acta neuropathologica communications 2022, Vol.10 (1), p.1-96, Article 96
Main Authors: Jiang, Richeng, Smailovic, Una, Haytural, Hazal, Tijms, Betty M., Li, Hao, Haret, Robert Mihai, Shevchenko, Ganna, Chen, Gefei, Abelein, Axel, Gobom, Johan, Frykman, Susanne, Sekiguchi, Misaki, Fujioka, Ryo, Watamura, Naoto, Sasaguri, Hiroki, Nyström, Sofie, Hammarström, Per, Saido, Takaomi C., Jelic, Vesna, Syvänen, Stina, Zetterberg, Henrik, Winblad, Bengt, Bergquist, Jonas, Visser, Pieter Jelle, Nilsson, Per
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer’s disease (AD) which is characterized by amyloid-β (Aβ) amyloidosis. Here, we used two App knock-in mouse models, App NL-F/NL-F and App NL-G-F/NL-G-F , exhibiting AD-like Aβ pathology to analyze how the brain pathologies translate to CSF proteomes by label-free mass spectrometry (MS). This identified several extracellular matrix (ECM) proteins as significantly altered in App knock-in mice. Next, we compared mouse CSF proteomes with previously reported human CSF MS results acquired from patients across the AD spectrum. Intriguingly, the ECM protein decorin was similarly and significantly increased in both App NL-F/NL-F and App NL-G-F/NL-G-F mice, strikingly already at three months of age in the App NL-F/NL-F mice and preclinical AD subjects having abnormal CSF-Aβ42 but normal cognition. Notably, in this group of subjects, CSF-decorin levels positively correlated with CSF-Aβ42 levels indicating that the change in CSF-decorin is associated with early Aβ amyloidosis. Importantly, receiver operating characteristic analysis revealed that CSF-decorin can predict a specific AD subtype having innate immune activation and potential choroid plexus dysfunction in the brain. Consistently, in App NL-F/NL-F mice, increased CSF-decorin correlated with both Aβ plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human Aβ42 induces decorin secretion from mouse primary neurons. Interestingly, we finally identify decorin to activate neuronal autophagy through enhancing lysosomal function. Altogether, the increased CSF-decorin levels occurring at an early stage of Aβ amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects.
ISSN:2051-5960
2051-5960
DOI:10.1186/s40478-022-01398-5