@article{01d9f019b6854891b78d9b9715b5e3bf,
title = "Increased CSF-decorin predicts brain pathological changes driven by Alzheimer{\textquoteright}s Aβ amyloidosis",
abstract = "Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimer{\textquoteright}s disease (AD) which is characterized by amyloid-β (Aβ) amyloidosis. Here, we used two App knock-in mouse models, AppNL-F/NL-F and AppNL-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 AppNL-F/NL-F and AppNL-G-F/NL-G-F mice, strikingly already at three months of age in the AppNL-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 AppNL-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.",
keywords = "Alzheimer{\textquoteright}s disease, Amyloid-β (Aβ), App knock-in mice, Autophagy, Cerebrospinal fluid, Choroid plexus, Decorin, Extracellular matrix, Mass spectrometry",
author = "Richeng Jiang and Una Smailovic and Hazal Haytural and Tijms, {Betty M.} and Hao Li and Haret, {Robert Mihai} and Ganna Shevchenko and Gefei Chen and Axel Abelein and Johan Gobom and Susanne Frykman and Misaki Sekiguchi and Ryo Fujioka and Naoto Watamura and Hiroki Sasaguri and Sofie Nystr{\"o}m and Per Hammarstr{\"o}m and Saido, {Takaomi C.} and Vesna Jelic and Stina Syv{\"a}nen and Henrik Zetterberg and Bengt Winblad and Jonas Bergquist and Visser, {Pieter Jelle} and Per Nilsson",
note = "Funding Information: Open access funding provided by Karolinska Institute. We thank the following financial support; H{\aa}llsten Research Foundation (PN), Swedish Research Council (PN), Swedish Brain foundation (PN), Torsten S{\"o}derberg Foundation (PN), Sonja Leikrans donation (PN), The Erling-Persson Family Foundation (PN), China Scholarship Council (RJ, HL), Swedish Research Council 2015-4870 (JB), European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk1odowska-Curie grant agreement number 676144 (Synaptic Dysfunction in Alzheimer Disease, SyDAD) (US, VJ, HH), Gun and Bertil Stohne{\textquoteright}s Foundation (US, HH, RJ), Gamla Tj{\"a}narinnor grant (US, VJ, PN, JG), Swedish Research Council 2015-4870 (JB), Margaretha af Ugglas Stiftelse (BW), Alzheimerfonden (#AF-930934) (JG), Alzheimerfonden and Hj{\"a}rnfonden (SS), Swedish Brain Foundation (#ALZ2022-0004, #FO-2020-0207) and Alzheimerfonden (#AF-929903) (PH, SN), Swedish Research Council (#2019-04405) (PH). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen f{\"o}r Gamla Tj{\"a}narinnor, Hj{\"a}rnfonden, Sweden (#FO2019-0228), the European Union{\textquoteright}s Horizon 2020 research and innovation programme under the Marie Sk{\l}odowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
day = "1",
doi = "https://doi.org/10.1186/s40478-022-01398-5",
language = "English",
volume = "10",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",
}