Choice cuts?
SOURCE: Nature Reviews Drug Discovery
signaling-gateway.org
Three new ground-breaking studies highlight possible new therapeutic strategies for Alzheimer's disease targeting the two enzymes — beta- and gamma-secretase — that produce amyloid-beta (Abeta) through sequential cleavage of the Abeta precursor protein.
Evidence for the key role of amyloid-beta (Abeta) in Alzheimer's disease has led to considerable interest in potential therapeutic strategies targeting two enzymes — beta- and gamma-secretase — that produce Abeta through sequential cleavage of the Abeta 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 beta2-adrenoceptor (beta2AR). Using cell-based assays, they found that beta2AR-activation increased secretion of Abeta, which was blocked by pretreatment with a gamma-secretase inhibitor. Subsequent experiments using an assay of the activity of gamma-secretase indicated that the beta2AR-agonist-induced increase in Abeta secretion was due to increased gamma-secretase activity.
Next, the authors probed the mechanism for enhanced gamma-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 beta2AR-induced gamma-secretase activity. So, beta2AR-induced enhancement of gamma-secretase activity is dependent on clathrin-mediated endocytosis. Further experiments revealed that the beta2AR directly associates with presenilin 1 — the catalytic subunit of g-secretase — which was trafficked to late endosomes and lysosomes where Abeta production was elevated.
Finally, Ni et al. studied the effects of beta2AR activation in rodents. Administration of either noradrenaline or a selective beta2AR agonist enhanced gamma-secretase activity and hippocampal Abeta levels in rats. Mice with cerebral amyloid plaques chronically treated with a selective beta2AR agonist had increased plaques, whereas mice treated with a selective beta2AR antagonist had reduced plaque levels.
Together, these results suggest a mechanism for the pathological role of stress in Alzheimer's disease, and indicate that betaAR 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 betaAR antagonists correlates with a decreased incidence of Alzheimer's disease.
The other two papers, in Science and Nature Neuroscience, focus on the beta-secretase enzyme, which in recent years has been viewed by some as a more promising target for reducing the pathological formation of Abeta than gamma-secretase, in part owing to the role of gamma-secretase in normal physiological processes. However, the physiological role of beta-secretase has not been clear.
To investigate this role, both Willem et al. and Hu et al. used beta-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 beta-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 beta-secretase is important in the maintenance of the mature myelin sheath, these studies suggest that beta-secretase inhibition for Alzheimer's disease should be approached with caution.
Charlotte Harrison |
