Choice cuts?
Three new ground-breaking studies highlight possible new therapeutic strategies for Alzheimer's disease targeting the two enzymes —  - and  -secretase — that produce amyloid- (A) through sequential cleavage of the A precursor protein.
Evidence for the key role of amyloid- (A) in Alzheimer's disease has led to considerable interest in potential therapeutic strategies targeting two enzymes — - and -secretase — that produce A through sequential cleavage of the A 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 2-adrenoceptor (2AR). Using cell-based assays, they found that 2AR-activation increased secretion of A, which was blocked by pretreatment with a -secretase inhibitor. Subsequent experiments using an assay of the activity of -secretase indicated that the 2AR-agonist-induced increase in A secretion was due to increased -secretase activity.
Next, the authors probed the mechanism for enhanced -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 2AR-induced -secretase activity. So, 2AR-induced enhancement of -secretase activity is dependent on clathrin-mediated endocytosis. Further experiments revealed that the 2AR directly associates with presenilin 1 — the catalytic subunit of g-secretase — which was trafficked to late endosomes and lysosomes where A production was elevated.
Finally, Ni et al. studied the effects of 2AR activation in rodents. Administration of either noradrenaline or a selective 2AR agonist enhanced -secretase activity and hippocampal A levels in rats. Mice with cerebral amyloid plaques chronically treated with a selective 2AR agonist had increased plaques, whereas mice treated with a selective 2AR antagonist had reduced plaque levels.
Together, these results suggest a mechanism for the pathological role of stress in Alzheimer's disease, and indicate that AR 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 AR antagonists correlates with a decreased incidence of Alzheimer's disease.
The other two papers, in Science and Nature Neuroscience, focus on the -secretase enzyme, which in recent years has been viewed by some as a more promising target for reducing the pathological formation of A than -secretase, in part owing to the role of -secretase in normal physiological processes. However, the physiological role of -secretase has not been clear.
To investigate this role, both Willem et al. and Hu et al. used -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 -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 -secretase is important in the maintenance of the mature myelin sheath, these studies suggest that -secretase inhibition for Alzheimer's disease should be approached with caution.
Charlotte Harrison
References
- Ni, Y. et al. Activation of 2-adrenergic receptor stimulates -secretase activity and accelerates amyloid plaque formation. Nature Med. 12, 1390 - 1396 (2006) | Article | PubMed |
- Willem, M. et al. Control of peripheral nerve myelination by the -secretase BACE1. Science 314, 664–666 (2006) | Article | PubMed |
- Hu, X. et al. Bace1 modulates myelination in the central and peripheral nervous system. Nature Neurosci. 9, 1520–1525 (2006) | Article | PubMed |
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