Raft disorganization leads to reduced plasmin activity in Alzheimer's disease brains

Abstract

The serine protease plasmin can efficiently degrade amyloid peptide in vitro, and is found at low levels in the hippocampus of patients with Alzheimer's disease (AD). The cause of such paucity remains unknown. We show here that the levels of total brain plasminogen and plasminogen-binding molecules are normal in these brain samples, yet plasminogen membrane binding is greatly reduced. Biochemical analysis reveals that the membranes of these brains have a mild, still significant, cholesterol reduction compared to age-matched controls, and anomalous raft microdomains. This was reflected by the loss of raft-enriched proteins, including plasminogen-binding and -activating molecules. Using hippocampal neurons in culture, we demonstrate that removal of a similar amount of membrane cholesterol is sufficient to induce raft disorganization, leading to reduced plasminogen membrane binding and low plasmin activity. These results suggest that brain raft alterations may contribute to AD by rendering the plasminogen system inefficient.

The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Aβ generation in vivo

“…Because seladin-1 is downregulated in vulnerable areas of brains in AD patients (Greeve et al, 2000), it is reasonable to think that low levels of seladin-1, promoted by yet to be identified causes, are responsible for the membrane cholesterol reduction found in such brains (Ledesma et al, 2003a). This would consequently lead to Ab accumulation via a combination of inefficient Ab degradation (due to low plasmin activity) and increased APP amyloidogenic cleavage.…”

“…Plasminogen binding to the membrane leads to the activation of the Ab-degrading enzyme plasmin in DRMs (Ledesma et al, 2003a). Therefore, we first investigated whether changes in seladin-1 expression affect plasminogen binding and plasmin activity in vivo.…”

“…The in vivo counterpart of the DRMs is under intense investigation. Experimental evidence has revealed the disorganization of DRMs in AD brains, possibly because of low cholesterol content (Ledesma et al, 2003a). In a recent study, it has been described that DRMs participate in the segregation of APP from BACE, therefore reducing APP b-cleavage and Ab production in cultured primary neurons and CHO cells, respectively (Abad-Rodriguez et al, 2004).…”

Lipid rafts, cholesterol, and the brain

“…Experimental evidence revealed that statins are capable of reducing amyloid β 42 deposition in animal models of AD (Refolo et al 2001). The analysis of temporal cortex from AD subjects showed loss of lipid rafts (MolanderMelin et al 2005), while hippocampi showed reduced cholesterol content in the rafts (Ledesma et al 2003). In addition the inhibition of cholesterol transport alters PS1 localization and APP processing in neuronal cells (Runz et al 2002).…”

Amyloid Hypothesis and Alzheimer's Disease

“…Plasmin, the active serine protease, is generated from tPA expressed in neurons and uPA expressed in neurons and microglial cells by cleavage of plasminogen (Madani et al, 2003). It is reported that plasmin significantly decreases the neurotoxicity of Aβ aggregation by degrading Aβ, which has been proved by cell culture (Ledesma et al, 2000;Ledesma et al, 2003) (Figure 2). Matrix metalloproteinases (MMPs) is a large family which can degrade and remodel extracellular matrix.…”