Choice cuts?

Evidence for the key role of amyloid-β (Aβ) in Alzheimer's disease has led to considerable interest in potential therapeutic strategies targeting two enzymes — β- and γ-secretase — that produce Aβ through sequential cleavage of the Aβ precursor protein. Three recent papers report findings that could have significant implications for these strategies.

In the first study, reported in Nature Medicine, Ni and colleagues sought to investigate how the pathogenesis of Alzheimer's disease is influenced by environmental factors such as stress, which is mediated by receptors including the β₂-adrenoceptor (β₂AR). Using cell-based assays, they found that β₂AR-activation increased secretion of Aβ, which was blocked by pretreatment with a γ-secretase inhibitor. Subsequent experiments using an assay of the activity of γ-secretase indicated that the β₂AR-agonist-induced increase in Aβ secretion was due to increased γ-secretase activity.

Next, the authors probed the mechanism for enhanced γ-secretase activity. After finding that activity enhancement was independent of cAMP signalling, they discovered that endocytosis inhibitors or small-interfering RNA against clathrin — a protein involved in the formation of endcytotic vesicles — abolished β₂AR-induced γ-secretase activity. So, β₂AR-induced enhancement of γ-secretase activity is dependent on clathrin-mediated endocytosis. Further experiments revealed that the β₂AR directly associates with presenilin 1 — the catalytic subunit of g-secretase — which was trafficked to late endosomes and lysosomes where Aβ production was elevated.

Finally, Ni et al. studied the effects of β₂AR activation in rodents. Administration of either noradrenaline or a selective β₂AR agonist enhanced γ-secretase activity and hippocampal Aβ levels in rats. Mice with cerebral amyloid plaques chronically treated with a selective β₂AR agonist had increased plaques, whereas mice treated with a selective β₂AR antagonist had reduced plaque levels.

Together, these results suggest a mechanism for the pathological role of stress in Alzheimer's disease, and indicate that βAR antagonists — which have long been widely used in cardiovascular disease therapy — might have therapeutic potential for Alzheimer's disease. This idea is supported by a recent study suggesting that the use of βAR antagonists correlates with a decreased incidence of Alzheimer's disease.

The other two papers, in Science and Nature Neuroscience, focus on the β-secretase enzyme, which in recent years has been viewed by some as a more promising target for reducing the pathological formation of Aβ than γ-secretase, in part owing to the role of γ-secretase in normal physiological processes. However, the physiological role of β-secretase has not been clear.

To investigate this role, both Willem et al. and Hu et al. used β-secretase-null (Bace1-null) mice. Lack of Bace1 resulted in the accumulation of unprocessed neuregulin 1, which is required for glial cell development and myelination. Together, their results indicate that β-secretase has a crucial role in the myelination of peripheral and central nerves during development. Although it remains to be determined whether the influence of β-secretase is important in the maintenance of the mature myelin sheath, these studies suggest that β-secretase inhibition for Alzheimer's disease should be approached with caution.