Increased CSF-decorin predicts brain pathological changes driven by Alzheimers A beta amyloidosis

Cerebrospinal fluid (CSF) biomarkers play an important role in diagnosing Alzheimers disease (AD) which is characterized by amyloid-beta (A beta) 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 A beta 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-A beta 42 but normal cognition. Notably, in this group of subjects, CSF-decorin levels positively correlated with CSF-A beta 42 levels indicating that the change in CSF-decorin is associated with early A beta 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 AP plaque load and with decorin levels in choroid plexus. In addition, a low concentration of human A beta 42 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 A beta amyloidosis in the brain may reflect pathological changes in choroid plexus, present in a subtype of AD subjects.
Funding Agencies|Karolinska Institute; Hallsten Research Foundation; Swedish Research Council; Swedish Brain foundation; Torsten Soderberg Foundation; Erling-Persson Family Foundation; China Scholarship Council; Swedish Research Council [2015-4870]; uropean Unions Horizon 2020 research and innovation program under the Marie Sk1odowska-Curie grant [676144]; Gun and Bertil Stohnes Foundation; Gamla Tjanarinnor grant; Margaretha af Ugglas Stiftelse; Alzheimerfonden [AF-930934]; Alzheimerfonden; Hjarnfonden; Swedish Brain Foundation [ALZ2022-0004, FO-2020-0207]; European Research Council [681712]; Swedish State Support for Clinical Research [ALFGBG-720931]; Alzheimer Drug Discovery Foundation (ADDF), USA [201809-2016862]; AD Strategic Fund; Alzheimers Association [ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C]; Olav Thon Foundation; Stiftelsen for Gamla Tjanarinnor, Hjarnfonden, Sweden [FO2019-0228]; European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [860197]; European Union Joint Program for Neurodegenerative Disorders [JPND2021-00694]; UK Dementia Research Institute at UCL