Vesna Jelic, Sweden
Karolinska Institutet Dept of Neurobiology, Care Sciences and SocietyAuthor Of 1 Presentation
EXTRACELLULAR MATRIX PROTEIN DECORIN IS INCREASED IN CSF OF APP KNOCK-IN MICE AND EARLY STAGE OF ALZHEIMER’S DISEASE
Abstract
Aims
Alzheimer’s disease (AD) brains are characterized by extracellular amyloid-beta (Aβ) deposition and autophagy dysregulation. Here we aimed at deepening the understanding of these brain pathologies and how they translate to the CSF.
Methods
AD postmortem brain tissues and App knock-in mouse models (AppNL-F and AppNL-G-F) were used for autophagy characterization. The cerebrospinal fluid (CSF) from App knock-in mice was analyzed by label-free mass spectrometry (MS) and compared with previously reported CSF MS results from patients. The expression of decorin in the mouse brains was analyzed by immunohistochemistry and western blot. The autophagy-activating effect of decorin was measured in the mouse primary neurons.
Results
p62 and LC3 II were increased in AppNL-G-F mice similar to the marked accumulation of p62 in AD brains. Several extracellular matrix (ECM) proteins, including decorin, were significantly increased in the CSF of both AppNL-Fmice and normal cognition a+t- human subjects. Decorin was mainly expressed in CA2 pyramidal neurons and parvalbumin-positive interneurons, the length of which was decreased in App knock-in mice. Decorin-treated mouse primary neurons exhibited lowered p62 and LC3 II levels.
Conclusions
Autophagy is similarly inhibited in the brains of AppNL-G-F mice and AD patients. Mice-human CSF alterations converge on several ECM proteins suggesting the alteration in blood brain barrier /blood CSF barrier composition. The ECM protein decorin activates neuronal autophagy by increasing autophagosomal-lysosomal degradation linking changes in ECM to autophagy.