Amyloid-β peptide (Aβ), which aggregates to form the plaques that are a feature of Alzheimer's disease (AD) brains, is a product of the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Data from two groups published in The Journal of Cell Biology identifies new control points in the APP processing pathway, manipulation of which could facilitate the development of treatments for this debilitating disease.

Several kinases that have been implicated in neurodegeneration catalyse the phosphorylation of threonine 668 (Thr668) of APP. As such, a team led by Li-Huei Tsai was prompted to investigate the role that this reaction might have in the development of AD. Their initial investigations revealed that phosphorylation of Thr668 was elevated in AD brains, particularly in the hippocampus. Subsequent immunolocalization studies showed that expression of Thr668-phosphorylated APP was coincident with that of hyperphosphorylated tau, tangles of which are another hallmark of AD brains.

Interestingly, Thr668-phosphorylated APP also colocalized with β-secretase (BACE1). This result hinted at a role for Thr668 phosphorylation in the regulation of BACE1 activity, a hypothesis that was lent credence when the production of Aβ was shown to be significantly reduced following inhibition of Thr668 phosphorylation. According to the authors, phosphorylation of Thr668 probably affects BACE1 activity indirectly by influencing the intracellular sorting and trafficking of APP and therefore its availability to the enzyme.

A more direct mechanism of regulation of BACE1 activity was demonstrated by Jeremy Turnbull and colleagues. This group wondered if heparan sulphate — proteoglycans of which are associated with Aβ plaques — might participate in Aβ production. In vitro assays showed that cleavage of APP by BACE1 was inhibited by heparan sulphate in a dose-dependent manner. Modification of the sulphation pattern of heparan sulphate and the number of saccharide monomers therein also influenced the degree of inhibition.

Affinity filter assays showed a direct interaction between heparan sulphate and BACE1. The authors suggest that, in the normal brain, endogenous heparan sulphate binds at or near the active site of BACE1, thereby preventing docking of its APP substrate, cleavage, and subsequent formation of Aβ fibrils. Perturbation of this interaction might contribute to the pathogenesis of AD, making it an attractive target for AD drug development.