Genotype-induced changes in biophysical properties of frontal cortex lipid raft from APP/PS1 transgenic mice

Abstract

Alterations in the lipid composition of lipid rafts have been demonstrated both in human brain and transgenic mouse models, and it has been postulated that aberrant lipid composition in lipid rafts is partly responsible for neuronal degeneration. In order to assess the impact of lipid changes on lipid raft functional properties, we have aimed at determining relevant physicochemical modifications in lipid rafts purified from frontal cortex of wild type (WT) and APP/PS1 double transgenic mice. By means of steady-state fluorescence anisotropy analyses using two lipid soluble fluorescent probes, TMA-DPH (1-[(4-trimethyl-amino)phenyl]-6-phenyl-1,3,5-hexatriene) and DPH (1,6-diphenyl-1,3,5-hexatriene), we demonstrate that cortical lipid rafts from WT and APP/PS1 animals exhibit different biophysical behaviors, depending on genotype but also on age. Thus, aged APP/PS1 animals exhibited slightly more liquid-ordered lipid rafts than WT counterparts. Membrane microviscosity ηapp analyses demonstrate that WT lipid rafts are more fluid than APP/PS1 animals of similar age, both at the aqueous interface and hydrophobic core of the membrane. ηapp in APP/PS1 animals was higher for DPH than for TMA-DPH under similar experimental conditions, indicating that the internal core of the membrane is more viscous than the raft membrane at the aqueous interface. The most dramatic changes in biophysical properties of lipid rafts were observed when membrane cholesterol was depleted with methyl-β-cyclodextrin. Overall, our results indicate that APP/PS1 genotype strongly affects physicochemical properties of lipid raft. Such alterations appear not to be homogeneous across the raft membrane axis, but rather are more prominent at the membrane plane. These changes correlate with aberrant proportions of sphingomyelin, cholesterol, and saturated fatty acids, as well as polyunsaturated fatty acids, measured in lipid rafts from frontal cortex in this familial model of Alzheimer's Disease.

Aβ promotes VDAC1 channel dephosphorylation in neuronal lipid rafts. Relevance to the mechanisms of neurotoxicity in Alzheimer’s disease

“…These evidences have been observed related to, both, AD and PD neuropathology, even at early stages of these diseases (Martı´n et al, 2010;Fabelo et al, 2011Fabelo et al, , 2014. A premature aberrant lipid composition in these microstructures has also been detected in APP/PS1 double-transgenic mice Diaz et al, 2012).…”

“…An emerging concept is that lipid rafts may evolve toward alterations in composition with aging . The progression of neurodegenerative diseases related to aging may exacerbate these lipid alterations, thereby inducing profound modifications in raft physicochemical properties (Martı´n et al, 2010;Diaz et al, 2012), that may largely affect protein interactions and trafficking. These evidences have been observed related to, both, AD and PD neuropathology, even at early stages of these diseases (Martı´n et al, 2010;Fabelo et al, 2011Fabelo et al, , 2014.…”

Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function

“…Alterations in MLR integrity due to oxidative stress[216], changes in lipid bilayer components that lead to altered MLR physiochemcial properties[217] or depletion in membrane cholesterol content[218, 219], not only alter cellular polarity[220], signal transduction[221], and morphology, but also can contribute to aberrant intercellular communication leading to organ pathology, including in the nervous system [166, 222, 223]. …”

Lipid Raft Alterations in Aged-Associated Neuropathologies

“…In this sense, alterations in the physicochemical properties of lipid rafts have been associated with modifications in lipid matrix composition that occurs with the progression of, both, AD and PD [18,19]. These changes affect, among others, the membrane order, domain packing and compressibility, [20,21] and, consequently, may constraint the proper interaction of raftintegrated proteins [22]. In line with this, it should be emphasized that physiological brain aging is also accompanied by a progressive modification in the molecular composition and structure of lipid rafts (coined as "lipid raft aging"), but this normal biological process appears to be accelerated during the development of brain neurodegenerative events [23].…”