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| Neurodegenerative diseases: Clearing up A | |||||||||||
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Amyloid-
degradation can be enhanced by activation of the plasmin protease cascade or increased lipidation of apolipoprotein E (ApoE).
The aggregation and deposition of amyloid- (A) peptides in the brain are thought to underlie the pathogenesis of Alzheimer's disease, and so therapeutic strategies to reduce A levels are being intensively pursued. Two recent studies highlight how modulation of pathways involved in the regulation of A levels can lead to enhanced degradation and clearance of A from the brain.
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In the first paper, published in Proceedings of the National Academy of Sciences, Jacobsen and colleagues investigated the role of plasmin — a protease that is generated from the cleavage of plasminogen by tissue plasminogen activator (tPA) — in the breakdown of A. By screening a compound library, the authors identified PAZ-417 as a potent and selective inhibitor of plasminogen activator inhibitor-1 (PAI-1), a known inhibitor of the plasmin cascade.
In vitro assays revealed that PAZ-417 augmented tPA, which led to plasmin generation and induced the cleavage of synthetic monomeric and oligomeric A. In a transgenic mouse model of Alzheimer's disease, PAI-1 inhibition led to a twofold increase in hippocampal tPA activity. Next, clearance of plasma and brain A was measured in two mouse models (plaque- and non-plaque-bearing ages), in which a single oral dose of PAZ-417 resulted in reduced plasma and brain A levels in both mouse types.
Administration of PAZ-417 to mice 24 hours before hippocampal slice preparation reversed the deficits in long-term potentiation that are associated with models of Alzheimer's disease, without altering neuronal function. Last, in a mouse model of hippocampal learning and memory, PAZ-417 reduced cognitive deficits, with complete reversal when given 24 hours before memory training.
The second study by Jiang and colleagues, reported in Neuron, looked at the mechanism by which the lipidation of apolipoprotein E (ApoE) affects A homeostasis. The authors first established that microglia are responsible for the uptake and degradation of soluble A, and co-incubation of purified human ApoE resulted in stimulation of A clearance from microglia, as a consequence of enhanced degradation. Treatment with an agonist of the liver X receptor (LXR), a nuclear receptor that has a key role in lipid metabolism, caused an increase of lipidated ApoE, resulting in enhanced degradation and lower levels of A. The combination of an LXR agonist and exogenous high-density apolipoproteins led to further reduction of A levels.
Next, it was shown that the lipidation status of ApoE influences its ability to promote A degradation, and influences the capacity of insulin-degrading enzyme to degrade A. In a transgenic mouse model of Alzheimer's disease, oral treatment with an LXR agonist for 4 months led to 50% fewer plaques and a reduction in plaque load, without altering amyloid precursor protein levels. Mice treated for 6 days with an LXR agonist had significantly improved contextual memory scores.
Together, these papers demonstrate that targeting two pathways that regulate A levels —ApoE lipidation or the plasmin cascade — with an LXR agonist or PAI-1 inhibitor, respectively — might have therapeutic potential in the treatment of Alzheimer's disease.
Charlotte Harrison
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