Cerebrospinal Fluid Proteins as Regulators of Beta-amyloid Aggregation and Toxicity

Abstract

Amyloid disorders, such as Alzheimer's, are almost invariably late-onset diseases. One defining diagnostic feature of Alzheimer's disease is the deposition of beta-amyloid as extracellular plaques, primarily in the hippocampus. This raises the question: are there natural protective agents that prevent beta-amyloid from depositing, and is it loss of this protection that leads to onset of disease? Proteins in cerebrospinal fluid (CSF) have been suggested to act as just such natural protective agents. Here, we describe some of the early evidence that led to this suggestion, and we discuss, in greater detail, two CSF proteins that have garnered the bulk of the attention.

Keywords: Alzheimer’s disease; amyloid beta-peptides; apolipoprotein E; glycoproteins; transthyretin.

Figure 1

(a) Structure of transthyretin (TTR) tetramer, showing putative sites of binding of Aβ. Two sites are highlighted: high-affinity strand G (red), with critical residue Leu110 drawn in detail, and low-affinity EF helix (blue), with critical residue Leu82 drawn in detail. (b) TTR tetramer showing putative binding sites along with TTR’s natural ligands, thyroxine (in the hydrophobic cavity in the center) and two molecules of retinol-binding protein (green). (c) A monomer of TTR, with strand G and adjacent strand H highlighted in red.