Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease

Abstract BackgroundThe pathological alterations of small arteries and capillaries defined as cerebral small vessel disease (CSVD) are characterized by age-dependent blood-brain barrier (BBB) breakdown and vessel wall remodeling manifesting in small vessel occlusions and perivascular bleeds. As collagen XVIII (Col18a1) is an abundant heparan sulfate proteoglycan in vascular basement membranes, we focused on studying the role of collagen XVIII in vascular integrity and neurovascular unit maintenance in the context of CSVD.MethodsIn this study, we examined BBB breakdown, neuroinflammation and (peri)synaptic protein alterations using immunohistochemistry in 5- and 12-month-old Col18a1-/- and Col18a1+/+ mice. To further characterize molecular alterations, we used qPCR and compared the expression levels of major genes encoding tight junction and basement membrane proteins, inflammatory markers, neural extracellular matrix (ECM) proteins and proteinases.ResultsOur immunohistochemical analysis revealed progression of small vessel leakage in Col18a1-/- mice between 5 and 12 months. A large fraction (60%) of the small vessel area became mouse IgG-immunopositive in the hippocampus and retrosplenial cortex of 12-month-old Col18a1-/- mice. However, none of the Col18a1-/- mice displayed hallmarks typical of more advanced stages of CSVD, such as perivascular or large bleeds or infarcts. Collagen XVIII deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, leading to perivascular ECM remodeling, upregulation of Timp3 and accumulation of perisynaptic ECM proteoglycan brevican and complement protein C1q, which may underlie impaired synaptic plasticity and loss of synapses.ConclusionOur findings highlight that Col18a1-/- mice represent a valuable model of early CSVD and call for more mechanistic analysis of underlying mechanisms and cognitive dysfunction in this model.