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Lipids in Protein Misfolding pp 67–94Cite as

Lipids in Amyloid-β Processing, Aggregation, and Toxicity

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 855))

Abstract

Aggregation of amyloid-beta (Aβ) peptide is the major event underlying neuronal damage in Alzheimer’s disease (AD). Specific lipids and their homeostasis play important roles in this and other neurodegenerative disorders. The complex interplay between the lipids and the generation, clearance or deposition of Aβ has been intensively investigated and is reviewed in this chapter. Membrane lipids can have an important influence on the biogenesis of Aβ from its precursor protein. In particular, increased cholesterol in the plasma membrane augments Aβ generation and shows a strong positive correlation with AD progression. Furthermore, apolipoprotein E, which transports cholesterol in the cerebrospinal fluid and is known to interact with Aβ or compete with it for the lipoprotein receptor binding, significantly influences Aβ clearance in an isoform-specific manner and is the major genetic risk factor for AD. Aβ is an amphiphilic peptide that interacts with various lipids, proteins and their assemblies, which can lead to variation in Aβ aggregation in vitro and in vivo. Upon interaction with the lipid raft components, such as cholesterol, gangliosides and phospholipids, Aβ can aggregate on the cell membrane and thereby disrupt it, perhaps by forming channel-like pores. This leads to perturbed cellular calcium homeostasis, suggesting that Aβ-lipid interactions at the cell membrane probably trigger the neurotoxic cascade in AD. Here, we overview the roles of specific lipids, lipid assemblies and apolipoprotein E in Aβ processing, clearance and aggregation, and discuss the contribution of these factors to the neurotoxicity in AD.

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Abbreviations

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

Aβ:

Amyloid-β peptide

CMC:

Critical micelle concentration

DHPC:

1,2-dihexanoyl-sn-glycero-3-phosphocholine

GM1:

Monosialotetrahexosyl ganglioside

HDL:

High-density lipoprotein

LRP1:

Low-density lipoprotein receptor-related protein

VLDLR:

Very low-density lipoprotein receptor

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Acknowledgements

The authors are very grateful to Prof. Gursky for her invaluable advice, writing assistance, critical review and proof reading of the chapter. This work was supported, in part, by Marie Curie International Outgoing Fellowship (IOF) 628077 “Structural and Biochemical Basis of Protein Amyloid Evolution” from the European Union to I. M.; M. G. acknowledges support from the BMBF Forschungsinitiative “BioEnergie 2021 - Forschung für die Nutzung von Biomasse” (0315487A-C) and the Cluster of Excellence “Tailor-made Fuels from Biomass” (EXC 236).

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  1. Isabel Morgado

    Present address: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA

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  1. Centre of Marine Sciences, University of Algarve, Faro, Portugal

    Isabel Morgado

  2. School of Medicine, Deakin University, Waurn Ponds, VIC, Australia

    Megan Garvey

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  1. Dept. of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA

    Olga Gursky

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Morgado, I., Garvey, M. (2015). Lipids in Amyloid-β Processing, Aggregation, and Toxicity. In: Gursky, O. (eds) Lipids in Protein Misfolding. Advances in Experimental Medicine and Biology, vol 855. Springer, Cham. https://doi.org/10.1007/978-3-319-17344-3_3

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