Clearance of amyloid β-peptide from brain: transport or metabolism?

To the editor

We read with interest the article by Iwata et al.¹ in the February 2000 issue of Nature Medicine suggesting a major degrading catabolic pathway for Alzheimer amyloid β-peptide (Aβ) in brain. Our own work, however, has indicated that, in addition to production of the peptide, transport of Aβ across the microvascular endothelium (that is, the site of the blood–brain barrier) is essential in controlling Aβ levels in the brain^2,3.

The physiological relevance of degradation mechanisms of Aβ described by Iwata et al.¹ remains unclear, as the peptide was studied at very high concentrations of about 240 μm/l, which may impair blood–brain barrier integrity^4,5. It is likely that Aβ at a concentration of 240 μm/l will cause plasma leakage into brain tissue. The size of the spot of Evans blue dye in the hippocampus and along the needle track shown by Iwata et al. (ref. 1, Fig. 1d) may translate into a volume of about 20–30 μl, much larger than the reported infusion volume of 0.5 μl. The invasive nature of the acute placement of 26-gauge needle used by Iwata et al.¹ very likely damages the blood–brain barrier. There is injury to blood vessels and microbleeding. Also, staining along the needle track indicates substantial reflux of injected material back to subarchnoid space, where contamination with cerebrospinal fluid is obvious. It is essential to place a small 33-gauge guiding cannula at least 3–5 days before infusing peptides to allow the tissue to recover from the trauma.

Finally, the affinity of neprilysin for its physiological substrates (such as enkephalins, tachykinins and atrial natriuretic peptide) and/or different synthetic peptides is in the low millimolar to micromolar range⁶. Normal levels of Aβ in the brain are in the low nanomolar ranges. Even in transgenic models of brain amyloidosis, brain levels of Aβ range from 40 nm/kg to 250 nm/kg from 3 to 12 months⁷. Several cell surface receptors in brain endothelial cells, microglia and/or neurons, including the receptor specific for advanced glycosylation end-products (RAGE), the scavenger type A receptor (SR-A; refs. 2,8), LRP-1 (low density lipoprotein receptor related protein) (ref. 9) and LRP-2 (ref. 3) bind Aβ with high nanomolar affinity directly (RAGE and SR-A) or indirectly (LRP-1 and LRP-2) through ligands such as α2M and apolipoproteins E and J, which act as high-affinity transport binding proteins for Aβ. Thus, in the intact brain, Aβ probably binds to several high-affinity cell surface receptors and/for binding proteins before being recognized by potential degrading enzymes.