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.

Amyloid Beta Peptide (Aβ1-42) Reverses the Cholinergic Control of Monocytic IL-1β Release

“…Later, it was shown that α4β2, α4α5β2, and α2αβ nAChRs can also interact with APP and its Aβ peptides [ 61 , 62 ]. In contrast to our data, however, the affinity of Aβ 1-42 to α7 nAChRs in the brain is in the low picomolar range [ 51 , 59 ].…”

“…APP and its Aβ peptides as well as nAChRs are evolutionary highly conserved and evolved long before the emergence of a nervous system [ 48 , 49 , 50 , 51 ], suggesting that their original functions need to be sought in more primitive and ubiquitous systems, such as innate immunity. Most research has investigated the pathophysiological effects of the interaction of Aβ with α7 nAChRs with a special focus on the etiology of AD [ 52 ].…”

“…The literature about the consequences of Aβ peptide binding to nAChRs is, however, contradictory [ 52 ]. Both, agonistic and antagonistic effects of Aβ peptides on the α7 nAChR have been described [ 15 , 16 , 51 , 52 , 67 , 68 , 69 , 70 , 71 ]. Moreover, we and others demonstrated that leukocytic nAChRs do not function as classical ion channels, but rather exert metabotropic functions [ 5 , 6 , 7 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ].…”

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…Here, the plasma membrane cell projection morphogenesis (p<3.98e-17) was significantly enriched. Biologically, this presents remarkable implications for the communication between cell types in the process of amyloid plaque formation [67]. The primary elements of SCZ include changes in cell shape and type rather than strict degradation, as demonstrated in AD-based enrichment.…”

Royal Jelly as an Intelligent Anti-Aging Agent—A Focus on Cognitive Aging and Alzheimer’s Disease: A Review

“…Longitudinal and autopsy studies suggest an important contribution of vascular mechanisms (small vessel disease) to cognitive decline in AD associated with type 2 diabetes mellitus [ 60 ]. Hyperglycemia induces vascular permeability by upregulating hypoxia inducible factor-1α (HIF-1α), which subsequently activates vascular endothelial growth factor (VEGF) [ 64 ]. Hyperglycemia also amplifies inflammatory and oxidative processes by contributing to the production of advanced glycation end-products (AGEs) through nonenzymatic glycation and oxidation of lipids, long-lived proteins, and nucleic acids.…”