Amyloid Precursor Protein Changes Arrangement in a Membrane and Its Structure Depending on the Cholesterol Content

Abstract

One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of amyloid beta (Aβ) peptides in the brain. The processing of amyloid precursor protein (APP) into Aβ is dependent on the location of APP in the membrane, membrane lipid composition and, possibly, presence of lipid rafts. In this study, we used atomic force microscopy (AFM) to investigate the interaction between transmembrane fragment APP672–726 (corresponding to Aβ1–55) and its amyloidogenic mutant L723P with membranes combining liquid-ordered and liquid-disordered lipid phases. Our results demonstrated that most of the APP672–726 is located either in the liquid-disordered phase or at the boundary between ordered and disordered phases, and hardly ever in rafts. We did not notice any major changes in the domain structure induced by APP672–726. In membranes without cholesterol APP672–726, and especially its amyloidogenic mutant L723P formed annular structures and clusters rising above the membrane. Presence of cholesterol led to the appearance of concave membrane regions up to 2 nm in depth that were deeper for wild type APP672–726. Thus, membrane cholesterol regulates changes in membrane structure and permeability induced by APP that might be connected with further formation of membrane pores.

The Influence of Lipid Electric Charge on the Binding of Aβ(1–42) Amyloid Peptide to Bilayers in the Liquid-Ordered State

“…The extent to which liquid-ordered and liquid-disordered (L d ) domains coexist in cell membranes, or even the mere existence of liquid-ordered (L o ) domains in cells, is still an object of debate [ 29 , 30 , 31 , 32 , 33 ]. For the specific case of Aβ–membrane interactions, Krasnobaev et al [ 7 ] observed, using atomic force microscopy, that transmembrane fragment APP672-726 (corresponding to Aβ1-55) is located either in the L d phase or at the boundary between ordered and disordered phases but not in L o domains. We already observed that L d bilayers consistently allowed a higher Aβ(1-42) binding than L o ones [ 15 ].…”

“…However, in recent studies, when a pure Aβ(1-40) peptide was mixed with monolayers of dipalmitoyl phosphatidylcholine (DPPC), which is known to undergo a temperature- and lateral pressure-dependent liquid-expanded-to-liquid-condensed bidimensional phase transition, the fibril-like structure of Aβ(1-40) appeared specifically in the liquid-expanded region [ 6 ]. Krasnobaev et al [ 7 ] used atomic force microscopy (AFM) to study the interaction of Aβ(1-55) with membrane bilayers containing liquid-ordered (L o ) and liquid-disordered (L d ) lipid domains. Most of the peptide was found either in the L d phase or at the boundary between ordered and disordered phases, in agreement with the data from Alvarez et al [ 6 ].…”

“…Several studies pointed out the facilitating role of GM1 ganglioside in Aβ oligomerization [ 8 , 9 , 10 , 11 ]. Cholesterol was also found to positively modulate Aβ oligomerization [ 7 , 12 ]. Oxysterols were proposed as the link between brain cholesterol metabolism and Alzheimer’s disease [ 13 ].…”