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Lipids in Amyloid-β Processing, Aggregation, and Toxicity

Chapter
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Amyloid-β peptide Alzheimer’s disease Cellular membranes and lipid rafts Cholesterol Gangliosides Peptide oligomers, protofibrils and fibrils Apolipoprotein E Amyloid precursor protein 

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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Notes

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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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Centre of Marine SciencesUniversity of AlgarveFaroPortugal
  2. 2.Department of Physiology and BiophysicsBoston University School of MedicineBostonUSA
  3. 3.School of MedicineDeakin UniversityWaurn PondsAustralia

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