47] Impairment of membrane transport and signal transduction systems by amyloidogenic proteins

Abstract

Proteins located within and associated with the plasma membrane and organellar membranes serve vital functions in essentially all cells. Two important types of membrane-associated proteins in neural cells are those involved in transporting various molecules (e.g., ions, nutrients, and neurotransmitters) across the membrane and those involved in transducing signals from different ligands (e.g., receptors for neurotransmitters, cytokines, and growth factors). Transporters in the plasma membrane include ion-motive ATPases such as Na + , K + –ATPase and Ca 2+ –ATPase, glucose transporters, and amino acid transporters. Membrane-associated proteins involved in signal transduction are remarkably complex, but can be placed into different categories such as receptors, guanosine triphosphate (GTP)-binding proteins, and effector proteins. Some membrane receptors are linked to GTP-binding proteins (e.g., muscarinic cholinergic receptors), others have intrinsic tyrosine kinase activity (e.g., neurotrophic factor receptors), and others are ion channels (e.g., ionotropic excitatory amino acid receptors). Amyloidogenic peptides can have a variety of adverse effects on cells ranging from modest dysfunction to overt cell death. This chapter describes methods for assessing the effects of amyloidogenic peptides on membrane transport and signal transduction systems and presents data illustrating the kinds of data that have arisen from such approaches. It focuses on the action of amyloid β-peptide (Aβ), a 40–42 amino acid peptide that accumulates as diffuse, and fibrillar deposits in the brains of individuals with Alzheimer's disease. However, available data suggest that the mechanisms described in this chapter also apply to other amyloidogenic proteins and their associated disorders, including amylin in diabetes, β2-microglobulin in systemic amy-loidosis, and prion proteins in Creutzfeld–Jacob disease and related disorders.