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

Abstract

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, 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.

Vascular endothelial‐cadherin as a marker of endothelial injury in preclinical Alzheimer disease

“…It will be important to validate these findings in larger longitudinal cohorts of preclinical AD from different centers, using other proteomic platforms, and to examine the relationship between endothelial injury markers and clinical or radiological disease progression, including brain atrophy and amyloid or tau aggregation, over time. As emerging data from animal studies support a role for various vascular constituents (e.g., endothelium, pericytes, fibroblasts, extracellular matrix, basement membrane proteins) in AD pathogenesis, 86 , 87 future clinical studies which can reliably measure changes to each of these vascular constituents, using novel biomarkers, will provide further insight into vascular contributions to AD onset and progression.…”

Plaque-associated endogenous IgG and its impact on immunohistochemical detection of mouse monoclonal IgG antibodies in mouse models of Alzheimer’s disease

“…Indeed, Whyte et al show specific detection of an Ms monoclonal IgG Ab against NeuN (MAB377, Millipore), which is also employed in this study, on paraffinized brain sections of App NL-G-F/NL-G-F mice using an anti-Ms IgG (H+L) secondary Ab 51 . Specific indirect detection on paraffin sections of App NL-G-F/NL-G-F mice using a secondary Ab against Ms IgG (H+L) has also been reported in IF for Parvalbumin, a marker for a subpopulation of cortical and hippocampal inhibitory interneurons 52 . IHC procedures on paraffin sections, such as dehydration, paraffin wax embedding, dewaxing, rehydration, and antigen retrieval, might disturb the antigen-antibody interaction between endogenous Ms IgG and secondary Abs against Ms IgG (H+L) that is preserved in frozen brain sections of AD mouse models.…”

Identification of biomarkers differentiating Alzheimer’s disease from other neurodegenerative diseases by integrated bioinformatic analysis and machine-learning strategies

“…Recent researches have shown that it also plays a critical role in autoimmune and inflammatory diseases ( Dong et al, 2022 ), antifibrotic ( Järvinen and Ruoslahti, 2019 ), antioxidant, and antiangiogenic properties ( Sofeu Feugaing et al, 2013 ; Järveläinen et al, 2015 ). DCN was found significantly increased in both AD mouse models and CSF of AD patients, predicting well innate immune activation and potential choroid plexus dysfunction ( Jiang et al, 2022 ). Other studies also demonstrated that endothelial-activated DCN-positive astrocytes contributed to vascular amyloid deposits but not parenchymal amyloid plaques in AD mouse models and AD/CAA patients ( Taylor et al, 2022 ).…”