Alzheimer's Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts

Abstract

Biological membranes show lateral and transverse asymmetric lipid distribution. Cholesterol (Chol) localizes in both hemilayers, but in the external one it is mostly condensed in lipid-ordered microdomains (raft domains), together with saturated phosphatidyl lipids and sphingolipids (including sphingomyelin and glycosphingolipids). Membrane asymmetries induce special membrane biophysical properties and behave as signals for several physiological and/or pathological processes. Alzheimer's disease (AD) is associated with a perturbation in different membrane properties. Amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein together with neuroinflammation and neurodegeneration are the most characteristic cellular changes observed in this disease. The extracellular presence of Aβ peptides forming senile plaques, together with soluble oligomeric species of Aβ, are considered the major cause of the synaptic dysfunction of AD. The association between Aβ peptide and membrane lipids has been extensively studied. It has been postulated that Chol content and Chol distribution condition Aβ production and posterior accumulation in membranes and, hence, cell dysfunction. Several lines of evidence suggest that Aβ partitions in the cell membrane accumulate mostly in raft domains, the site where the cleavage of the precursor AβPP by β- and γ- secretase is also thought to occur. The main consequence of the pathogenesis of AD is the disruption of the cholinergic pathways in the cerebral cortex and in the basal forebrain. In parallel, the nicotinic acetylcholine receptor has been extensively linked to membrane properties. Since its transmembrane domain exhibits extensive contacts with the surrounding lipids, the acetylcholine receptor function is conditioned by its lipid microenvironment. The nicotinic acetylcholine receptor is present in high-density clusters in the cell membrane where it localizes mainly in lipid-ordered domains. Perturbations of sphingomyelin or cholesterol composition alter acetylcholine receptor location. Therefore, Aβ processing, Aβ partitioning, and acetylcholine receptor location and function can be manipulated by changes in membrane lipid biophysics. Understanding these mechanisms should provide insights into new therapeutic strategies for prevention and/or treatment of AD. Here, we discuss the implications of lipid-protein interactions at the cell membrane level in AD.

Keywords: Alzheimer’s disease; Aβ peptide; acetylcholinesterase; cell membranes; cholesterol; lipid rafts; nicotinic acetylcholine receptor.

FIGURE 1

Schematic diagram showing two distinct hypotheses of APP processing, which differ in the membrane location of the whole process. Two different colors are used to represent a raft domain and a liquid-disordered domain (light blue and gray, respectively). (a) Hypothesis where β sec is present in both raft and non-raft domains but needs to be in raft domains to be functional (represented as β sec^*) (Ehehalt et al., 2003). (b) Hypothesis where β sec in raft domains corresponds to an inactive pool that needs to relocate to non-raft domains to be functional (Abad-Rodriguez et al., 2004). APP, amyloid precursor protein; α-CTF, C-terminal fragment obtained by α-secretase; α-APPsec, soluble N-terminal APP fragment obtained by α-secretase; Aβ, amyloid β peptide; β-APPsec, soluble N-terminal APP fragment obtained by β-secretase; AICD, APP intracellular domain obtained by the action of γ-secretase on β-CTF or C99 (intermediate peptide that is not shown and corresponds to Aβ plus AICD, obtained in the first step by the action of β-secretase); α-sec, α-secretase; β-sec, β-secretase; and γ-sec, γ-secretase.

FIGURE 2

Schematic diagram showing three different hypotheses of AD, which are closely related. Two different colors are used to represent a raft domain and a liquid-disordered domain (light blue and gray, respectively), and also within raft domains, two central lipids are identified for these hypotheses with different colors: chol and GM1 (green and blue, respectively). Aβ, amyloid β peptide; α7 nAChR, α7 nicotinic acetylcholine receptor.

FIGURE 3

Schematic diagram of a plasma membrane, depicting the spatial relationship between the molecules involved in Aβ synthesis and the cholinergic system. Two different colors are used to represent a raft domain and a liquid-disordered domain (light blue and gray, respectively). APP, amyloid precursor protein; Aβ, amyloid β peptide; α7 nAChR, α7 nicotinic acetylcholine receptor; ACE_T, tetrameric acetylcholinesterase; α-sec, α-secretase; β-sec, β-secretase; γ-sec, γ-secretase; and PRiMA, proline-rich membrane anchor.