Imbalance in Fatty-Acid-Chain Length of Gangliosides Triggers Alzheimer Amyloid Deposition in the Precuneus

Abstract

Amyloid deposition, a crucial event of Alzheimer’s disease (AD), emerges in distinct brain regions. A key question is what triggers the assembly of the monomeric amyloid ß-protein (Aß) into fibrils in the regions. On the basis of our previous findings that gangliosides facilitate the initiation of Aß assembly at presynaptic neuritic terminals, we investigated how lipids, including gangliosides, cholesterol and sphingomyelin, extracted from synaptic plasma membranes (SPMs) isolated from autopsy brains were involved in the Aß assembly. We focused on two regions of the cerebral cortex; precuneus and calcarine cortex, one of the most vulnerable and one of the most resistant regions to amyloid deposition, respectively. Here, we show that lipids extracted from SPMs isolated from the amyloid-bearing precuneus, but neither the amyloid-free precuneus nor the calcarine cortex, markedly accelerate the Aß assembly in vitro. Through liquid chromatography-mass spectrometry of the lipids, we identified an increase in the ratio of the level of GD1b-ganglioside containing C20:0 fatty acid to that containing C18:0 as a cause of the enhanced Aß assembly in the precuneus. Our results suggest that the local glycolipid environment play a critical role in the initiation of Alzheimer amyloid deposition.

Differential Anatomical Expression of Ganglioside GM1 Species Containing d18:1 or d20:1 Sphingosine Detected by MALDI Imaging Mass Spectrometry in Mature Rat Brain

“…In the same study, the spatio-temporal expression profiles of d18:1 and d20:1 species of GD1, GT1, GM2, and GM3 were also specific to the sphingosine chain length following ischemia. The biological relevance of the ceramide moiety of gangliosides was recently confirmed in a study where the c18:0 and c20:0 fatty acid species of GD1b were shown to have differential effects on the assembly of amyloid protein ( Oikawa et al, 2015 ). Likewise, GM1d18:1 and GM1d20:1 were upregulated to slightly different degrees in a combined model of Amyloid Beta load and striatal ischemia ( Caughlin et al, 2015 ).…”

“…Studies focusing on the ceramide moiety of gangliosides in the brain are relatively scarce, but important discoveries reported recently point toward a functionally distinct role for these different ganglioside species ( Sugiura et al, 2008 ; Whitehead et al, 2011 ; Oikawa et al, 2015 ). Based on the biochemical differences between d18:1- and d20:1-sphingosine molecules in the ceramide base, it has been suggested that the different species influence local membrane fluidity differentially, with a longer sphingosine tail making the membrane flatter and more rigid ( Sonnino and Chigorno, 2000 ).…”

Amyloid-β fibrils assembled on ganglioside-enriched membranes contain both parallel β-sheets and turns

“…The GM1-enriched membrane was incubated with 10 M seed-free soluble A␤ 40 in PBS for 15 min to 72 h at 37°C (30,31). After washing three times with PBS, the membrane was imaged at 25°C in water using an SPM-9600 atomic force microscope (Shimadzu Corp., Kyoto, Japan) and a 38-m soft cantilever (BL-AC40TS-C2, Olympus, Tokyo, Japan) with integrated pyramidal silicon nitride tips with spring constant 0.1 N m Ϫ1 .…”

“…More recently, atomic force microscopy (AFM) of a reconstituted lipid bilayer containing mouse synaptosomal lipids has suggested that A␤-sensitive ganglioside nanoclusters promote A␤ 40 assembly (29,30). In addition, the chain length of ganglioside GD1b was found to influence A␤ 42 assembly at the neuronal membrane in human precuneus with amyloids (31).…”

Polyunsaturated Fatty Acid Composition of Cerebrospinal Fluid Fractions Shows Their Contribution to Cognitive Resilience of a Pre-symptomatic Alzheimer’s Disease Cohort

“…Fatty acyls are a major component of membrane lipids and can influence AD pathology in several ways. Palmitoylation of APP influences Aβ 42 formation (Bhattacharyya et al, 2013;Andrew et al, 2017), and the ratios of different fatty acids in gangliosides have been shown to influence aggregation of Aβ 42 (Oikawa et al, 2009;Oikawa et al, 2015). The fatty acyl composition of cellular membranes contributes to their physical properties and the activities of transmembrane proteins.…”