Journal Article

DZNE-2024-00325

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease.

Khoshneviszadeh, M. (First author)DZNE* ; Henneicke, S.DZNE* ; Pirici, D. ; Senthilnathan, A.DZNE* ; Morton, L. ; Arndt, P.DZNE* ; Kaushik, R.DZNE* ; Norman, O. ; Jukkola, J. ; Dunay, I. R. ; Seidenbecher, C. ; Heikkinen, A. ; Schreiber, S.DZNE* ; Dityatev, A. (Last author)DZNE*

2024
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.matbio.2024.02.007

Abstract: Collagen type XVIII (COL18) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of COL18 would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed brain-wide in capillaries and arterioles. BBB permeability increased with age and affected cortical regions and the hippocampus in 12-month-old Col18a1-/- mice. None of the Col18a1-/- mice displayed hallmarks of advanced CSVD, such as hemorrhages, and did not show perivascular space enlargement. Col18a1 deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. We verified the pivotal role of COL18 for small vessel wall structure in CSVD by demonstrating the protein's involvement in vascular remodeling in autopsy brains from patients with cerebral hypertensive arteriopathy. Our study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.

Keyword(s): Collagen Type XVIII: genetics (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Animals (MeSH) ; Infant (MeSH) ; Mice, Knockout (MeSH) ; Neuroinflammatory Diseases (MeSH) ; Extracellular Matrix: metabolism (MeSH) ; Collagen Type XVIII: metabolism (MeSH) ; Heparan Sulfate Proteoglycans: metabolism (MeSH) ; Endostatins (MeSH) ; Cerebral Small Vessel Diseases: genetics (MeSH) ; Cerebral Small Vessel Diseases: metabolism (MeSH) ; COL18A1 protein, human ; Brevican ; Collagen XVIII ; Extracellular matrix ; Microglia ; Neuroinflammation ; Small vessel disease ; TIMP-3 ; Collagen Type XVIII ; Heparan Sulfate Proteoglycans ; Endostatins

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Contributing Institute(s):

1. Molecular Neuroplasticity (AG Dityatev)
2. Mixed Cerebral Pathologies and Cognitive Aging (AG Schreiber)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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