Membrane dynamics, cholesterol homeostasis, and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the deposition of ␤ -amyloid (A ␤ ) plaques derived from the amyloidogenic processing; of a transmembrane protein called ␤ -amyloid precursor protein (APP). In addition to the known genetic/sporadic factors that promote the formation of A ␤ , the composition and structural dynamics of the membrane are also thought to play a significant role in the amyloidogenic processing of APP that promotes seeding of A ␤ . This minireview reinforces the roles played by membrane dynamics, membrane microdomains, and cholesterol homeostasis in relation to amyloidogenesis, and reviews current strategies of lowering cholesterol in treating AD. -N STRUCTURE OF CELL MEMBRANEBiological membranes play a critical role in carrying out almost all physiological functions of the cell. The molecular organization of the cell membrane forms an infrastructural basis for all specialized function(s) carried out by the cell membrane. Many model membranes of varying molecular organization have been hypothesized and proposed to justify membrane functions (1-4). Among these, a dynamic fluid mosaic model (5) that evolved after several hypothetical modifications (6-8) has become a widely accepted model applicable to most biological membranes. Fluid mosaic model of cell membraneAccording to this classic model, membrane is composed of a bulk of phospholipid organized as a bilayer, with globular integral proteins embedded within the phospholipid texture. Phospholipids are arranged with their ionic and polar head groups in direct contact with the aqueous phase at the exterior and interior surfaces of the bilayer ( Fig. 1 , black gradient-filled circles), thereby maximizing hydrophilic interactions at the aqueous surfaces, while the nonpolar saturated fatty acid chains interdigitate within the interior of the membrane bilayer, forming a matrix (5). Voids and spaces between these chain aggregates are filled with lipids, of which cholesterol constitutes a major component (9, 10). The lipid matrix of the model membrane exists in three different phases, i.e., gel, liquid-ordered, and liquid-disordered states, in order of increasing fluidity (11). In the gel state, lipids are semifrozen; in the liquid-ordered state, lipids are viscous; and in the liquid-disordered state, lipids exist as fluids. This liquid-disordered fluid phase is essential for protein functions (12). The liquid-disordered fluid phase can be transformed to the liquid-ordered or gel state by tight packing of phospholipids and hydrocarbon chains with cholesterol intercalations in order of increasing rigidity (9). Thus, the amount of cholesterol present in the membrane determines the fluid/rigid state of the membrane.Integral membrane proteins [membrane anchor proteins, i.e., glycophosphatidylinositol (GPI), Src -family proteins, receptor ligands, signaling molecules, transmembrane proteins] are embedded within the phospholipid bilayer with their ionic and highly polar groups protruding to the exterior surface, and nonpolar groups largely bur...

Using model membranes for the study of amyloid beta:lipid interactions and neurotoxicity

“…Lipid rafts are small ( 70 nm), dynamic and heterogeneous microdomains that compartmentalize cellular processes (Chauhan, 2003). The constituent lipids in rafts are in a biophysical state comparable to the L o state of model membranes (Hanzal-Bayer and Hancock, 2007).…”

“…The sphingolipid molecules associate with each other via their head groups and within the bilayer through the saturated hydrocarbon chains. The chains are interconnected with each other by the intercalating properties of cholesterol which resides in between them (Chauhan, 2003). The L d bilayer is composed mainly of glycerophospholipids.…”

“…The figure shows how clustering of proteins which have a high affinity for lipid rafts could cause either small rafts containing the protein to coalesce into larger rafts (I) or increase the overall affinity of the protein cluster enough to recruit it to rafts (II) (Brown and London, 2000). Once understood as playing a part in cellular mechanisms such as inter-cellular trafficking of lipids and lipid-anchored proteins, rafts are now considered essential components of physiological functions such as cell adhesion, cell sorting, membrane traffic and as docking sites for cellular signaling (Chauhan, 2003;Hanzal-Bayer and Hancock, 2007).…”

“…This eventually leads to accumulation of Ab. Under other nongenetic circumstances such as high cholesterol, there is a change in membrane fluidity/dynamics, and other effects due to increased cholesterol may lead to increased production of Ab, leading to poor clearance and subsequent accumulation (Chauhan, 2003).…”

“…Although not fully understood, a few molecular mechanisms have been proposed: High levels of cholesterol (i) decrease membrane fluidity. This change affects the lateral movement of both APP and a-secretase in a way that disfavors their interaction (Chauhan, 2003;Kojro et al, 2001); (ii) promote/favor APP internalization and decreases the amount of APP at the surface, thus decreasing access of a-secretase to APP. There is a view that a-secretase activity is principally localized on the cell surface, explaining why APP endocytosis lowers APP cleavage by a-secretase (Chauhan, 2003;Kojro et al, 2001); (iii) interferes with APP maturation (probably glycosylation).…”