Complex and Multidimensional Lipid Raft Alterations in a Murine Model of Alzheimer's Disease

Wayne Chadwick,Randall Brenneman,Stuart Maudsley,Bronwen Martin

doi:10.4061/2010/604792

Abstract

Various animal models of Alzheimer's disease (AD) have been created to assist our appreciation of AD pathophysiology, as well as aid development of novel therapeutic strategies. Despite the discovery of mutated proteins that predict the development of AD, there are likely to be many other proteins also involved in this disorder. Complex physiological processes are mediated by coherent interactions of clusters of functionally related proteins. Synaptic dysfunction is one of the hallmarks of AD. Synaptic proteins are organized into multiprotein complexes in high-density membrane structures, known as lipid rafts. These microdomains enable coherent clustering of synergistic signaling proteins. We have used mass analytical techniques and multiple bioinformatic approaches to better appreciate the intricate interactions of these multifunctional proteins in the 3xTgAD murine model of AD. Our results show that there are significant alterations in numerous receptor/cell signaling proteins in cortical lipid rafts isolated from 3xTgAD mice.

Highlights

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders amongst adults of advanced age, and it is the most common form of dementia and cognitive impairment [1, 2]
Our results show that there are significant alterations in numerous receptor/cell signaling proteins in cortical lipid rafts isolated from 3xTgAD mice
Using our informatic receptor-targeted approach, we were able to reinforce the validity of our discovery process by identifying the importance of energy-related insulin/insulinlike growth factor (IGF) signaling in AD (Figures 3(j), 3(n), 5, and 8(d)) that has recently become more widely appreciated by other researchers [39,40,41,42]

Summary

Introduction

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders amongst adults of advanced age, and it is the most common form of dementia and cognitive impairment [1, 2]. ApoE4 has been strongly correlated with the generation of AD symptomatology Both of the amyloidogenic processing enzymes (β- and γ-secretase), as well as APP, are all enriched in lipid raft membranes [13, 14]. Association of Aβ plaques to lipid rafts can mediate recruitment of excess Fyn to the rafts, as well as further recruitment and phosphorylation of tau These activities are thought to induce neurotoxicity via the effects of tau-induced changes in the actin cytoskeleton and receptor/cellular signaling pathways [21]. Our study demonstrates that cortical lipid rafts are profoundly affected in the 3xTgAD mice and that many of the neurophysiological deficits characteristic of AD (impaired synaptic strength, impaired learning and memory, and increased oxidative stress) can be strongly linked to changes in receptor and cell signaling events in the lipid rafts in these animals. The lipid raft environments can be seen as one of the most important pathophysiological loci of this disorder

Methods

Findings

Discussion

Conclusion