Proteolytic fragments of laminin promote excitotoxic neurodegeneration by up-regulation of the KA1 subunit of the kainate receptor

Abstract

Degradation of the extracellular matrix (ECM) protein laminin contributes to excitotoxic cell death in the hippocampus, but the mechanism of this effect is unknown. To study this process, we disrupted laminin γ1 (lamγ1) expression in the hippocampus. Lamγ1 knockout (KO) and control mice had similar basal expression of kainate (KA) receptors, but the lamγ1 KO mice were resistant to KA-induced neuronal death. After KA injection, KA1 subunit levels increased in control mice but were unchanged in lamγ1 KO mice. KA1 levels in tissue plasminogen activator (tPA)–KO mice were also unchanged after KA, indicating that both tPA and laminin were necessary for KA1 up-regulation after KA injection. Infusion of plasmin-digested laminin-1 into the hippocampus of lamγ1 or tPA KO mice restored KA1 up-regulation and KA-induced neuronal degeneration. Interfering with KA1 function with a specific anti-KA1 antibody protected against KA-induced neuronal death both in vitro and in vivo. These results demonstrate a novel pathway for neurodegeneration involving proteolysis of the ECM and KA1 KA receptor subunit up-regulation.

Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation

“…As most established tPA functions in the adult brain are mediated through plasmin (Pang et al, 2004; Chen et al, 2008; Echeverry et al, 2010), we determined the effects of both tPA and plasmin on reelin processing (Fig. 2A) by incubating reelin (50 nM) with tPA (50 nM), plasminogen (18 μg/μl), plasminogen and tPA or purified plasmin (0.5 U/ml) for 15 and 45 min.…”

Plasmin deficiency leads to fibrin accumulation and a compromised inflammatory response in the mouse brain

“…Brain sections from mice exposed to an intrahippocampal kainate-injection [15] were used as positive control for FJC immunostaining. Replacement of the primary antibodies by PBS served as negative controls for all stainings.…”

Ablation of astrocytic laminin impairs vascular smooth muscle cell function and leads to hemorrhagic stroke

“…To investigate whether knocking out neuronal laminin 1 could affect vascular laminins, we analyzed the expression of different laminin chains (1, 2, and 4) in CaMKII-Cre/laminin 1 conditional KO and littermate control mice (neuron-specific laminin 1 KO; Chen et al, 2008). There was no change in laminin expression in the vasculature between control and CaMKII-Cre/laminin 1 KO mice (Fig.…”