Extracellular Matrix Changes in Subcellular Brain Fractions and Cerebrospinal Fluid of Alzheimer’s Disease Patients

Author:

Höhn Lukas12,Hußler Wilhelm12,Richter Anni13ORCID,Smalla Karl-Heinz145ORCID,Birkl-Toeglhofer Anna-Maria67ORCID,Birkl Christoph8ORCID,Vielhaber Stefan24,Leber Stefan L.9ORCID,Gundelfinger Eckart D.145ORCID,Haybaeck Johannes67,Schreiber Stefanie2410ORCID,Seidenbecher Constanze I.134

Affiliation:

1. Leibniz Institute for Neurobiology (LIN), 39118 Magdeburg, Germany

2. Department of Neurology, Otto-von-Guericke University, 39120 Magdeburg, Germany

3. Center for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Jena-Magdeburg-Halle, 07743 Jena, Germany

4. Center for Behavioral Brain Sciences (CBBS), 39104 Magdeburg, Germany

5. Institute for Pharmacology and Toxicology, Otto-von-Guericke-University, 39120 Magdeburg, Germany

6. Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria

7. Diagnostic and Research Center for Molecular Biomedicine, Institute of Pathology, Medical University of Graz, 8036 Graz, Austria

8. Department of Neuroradiology, Medical University of Innsbruck, 6020 Innsbruck, Austria

9. Division of Neuroradiology, Vascular and Interventional Radiology, Medical University of Graz, 8036 Graz, Austria

10. German Center for Neurodegenerative Disorders (DZNE), 39120 Magdeburg, Germany

Abstract

The brain’s extracellular matrix (ECM) is assumed to undergo rearrangements in Alzheimer’s disease (AD). Here, we investigated changes of key components of the hyaluronan-based ECM in independent samples of post-mortem brains (N = 19), cerebrospinal fluids (CSF; N = 70), and RNAseq data (N = 107; from The Aging, Dementia and TBI Study) of AD patients and non-demented controls. Group comparisons and correlation analyses of major ECM components in soluble and synaptosomal fractions from frontal, temporal cortex, and hippocampus of control, low-grade, and high-grade AD brains revealed a reduction in brevican in temporal cortex soluble and frontal cortex synaptosomal fractions in AD. In contrast, neurocan, aggrecan and the link protein HAPLN1 were up-regulated in soluble cortical fractions. In comparison, RNAseq data showed no correlation between aggrecan and brevican expression levels and Braak or CERAD stages, but for hippocampal expression of HAPLN1, neurocan and the brevican-interaction partner tenascin-R negative correlations with Braak stages were detected. CSF levels of brevican and neurocan in patients positively correlated with age, total tau, p-Tau, neurofilament-L and Aβ1-40. Negative correlations were detected with the Aβ ratio and the IgG index. Altogether, our study reveals spatially segregated molecular rearrangements of the ECM in AD brains at RNA or protein levels, which may contribute to the pathogenic process.

Funder

Deutsche Forschungsgemeinschaft

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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