Alzheimer 2013 Jun-3

 

Biochemical identification of a linear cholesterol-binding domain within Alzheimer’s β amyloid peptide.

ACS Chem Neurosci. 2013 Mar 20;4(3):509-17

Di Scala C, Yahi N, Lelièvre C, Garmy N, Chahinian H, Fantini J.

Laboratoire PPSN, EA 4674, Interactions Moléculaires et Systèmes Membranaires, Faculté des Sciences de St-Jérôme, Aix-Marseille Université, Service 331, 13331 Marseille cedex 20, France.

Abstract

Alzheimer’s β-amyloid (Aβ) peptides can self-organize into amyloid pores that may induce acute neurotoxic effects in brain cells. Membrane cholesterol, which regulates Aβ production and oligomerization, plays a key role in this process. Although several data suggested that cholesterol could bind to Aβ peptides, the molecular mechanisms underlying cholesterol/Aβ interactions are mostly unknown. On the basis of docking studies, we identified the linear fragment 22-35 of Aβ as a potential cholesterol-binding domain. This domain consists of an atypical concatenation of polar/apolar amino acid residues that was not previously found in cholesterol-binding motifs. Using the Langmuir film balance technique, we showed that synthetic peptides Aβ17-40 and Aβ22-35, but not Aβ1-16, could efficiently penetrate into cholesterol monolayers. The interaction between Aβ22-35 and cholesterol was fully saturable and lipid-specific. Single-point mutations of Val-24 and Lys-28 in Aβ22-35 prevented cholesterol binding, whereas mutations at residues 29, 33, and 34 had little to no effect. These data were consistent with the in silico identification of Val-24 and Lys-28 as critical residues for cholesterol binding. We conclude that the linear fragment 22-35 of Aβ is a functional cholesterol-binding domain that could promote the insertion of β-amyloid peptides or amyloid pore formation in cholesterol-rich membrane domains.

PMID: 23509984

 

Supplement picture:

Jacques Fantini-2 correct one

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