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

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.

Leucine Carboxyl Methyltransferase 1 (LCMT1)-dependent Methylation Regulates the Association of Protein Phosphatase 2A and Tau Protein with Plasma Membrane Microdomains in Neuroblastoma Cells

“…Using detergent-free procedures, we first show that PP2A A, B␣, and C subunits are present in membrane rafts from N2a cells. These findings are consistent with earlier studies reporting the presence of PP2A subunits in CEMs purified from nonneuronal cell types (28,49) and in detergent-resistant membranes isolated from normal mouse cortical tissue (5). Besides B␣ subunits, other regulatory B subunits not studied here may also be present in rafts.…”

“…There is increasing evidence that missorting and altered compartmentalization of key proteins such as Tau in raft and non-raft membrane microdomains play a critical role in neurodegenerative disorders, including AD pathogenesis (6). Significant alterations in cortical lipid raft composition have been recently reported in mouse models of AD (5). Of particular interest in this proteomic study is the observation that PP2A/B␣ holoenzymes were identified in the group of lipid raft proteins regulating key signaling pathways and synaptic-dependent processes such as axonal guidance and long term depression, which became significantly down-regulated in AD mouse models.…”

“…Dynamic rearrangement of membrane microdomains leading to localized protein clustering or dissociation has been linked to generation of signal transduction cascades in both normal and pathophysiological conditions (3,4). Significantly, alterations in the composition of membrane raft and non-raft microdomains are associated with AD pathogenesis (5,6). Both the microtubule-associated protein Tau and the amyloid precursor proteins, which play a central role in the disease, can be recruited to membrane rafts (7).…”

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

“…To test this hypothesis, we examined the Ephrin receptor A7 (EphA7), which is also localized in lipid rafts (47). COS-7 cells were either cotransfected with Epha7-HA and ApoER2 or transfected with ApoER2-HA and ApoER2 constructs and then treated with Reelin.…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…Similarly, PLD3 putative loss-of-function polymorphisms have been reported to correlate with increased risk of AD in African Americans ( 81 ). Independent of the coding variants, PLD3 protein expression is downregulated in AD brains ( 84 ) and in cortical membrane lipid rafts prepared from the 3xTgAD murine model of AD ( 85 ).…”