Chen R, Zhang J, Wu Y, Wang D, Feng G, Tang YP, Teng Z, Chen C.
Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease.
Cell Rep. 2012 Nov 29;2(5):1329-39.
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This paper provides convincing data that inhibition of monoacylglycerol lipase by JZL184 can prevent neuroinflammation and improve synaptic plasticity and memory in AD mice. The authors used a number of innovative techniques. However, since arachidonic acid (AA) release can be mediated by other enzymes, including phospholipases, which are probably more abundant than the monoacylglycerol lipase, it is not clear how this enzyme is linked specifically to AA-derived prostaglandins in the AD brain. It is possible that, besides being an inhibitor of the lipase, JZL184 may have anti-inflammatory and antioxidative properties. Also, it may be good to consider a possible link between endocannabinoids and AD.
The importance of this paper lies in the proof of principle that lipid cascades can be pharmaceutically targeted. Neurolipidomic studies to date have identified multiple key lipid metabolic pathways that appear to act as determinants of AD pathology, yet the million-dollar question has always been, How can specific metabolic pathways be targeted without massive systemic imbalance? Chen et al. show, perhaps for the first time, that pharmaceutical intervention into lipid metabolism indeed alters disease progression, at least in rapid-onset mouse models of AD. Excitingly, the far-reaching effects in this model of MAGL inhibition support Herrup's hypothesis (2010) that a defining "change of state," envisioned as a systemic metabolic change that accelerates cognitive decline, in part, by rendering neurons susceptible to the synaptotoxic and neurotoxic effects of Aβ, may be one of aberrant lipid metabolism. It will be important to understand the impact of MAGL inhibition on multiple pathways and on combination therapy. Clinical trials of early lipid modulators have not met with significant success, but tweaking the pathway modulation (i.e., riding the wave of this lipid change of state) to promote a "normal biology" represents a new frontier for AD research. Here, critical assessment of circulating biomarkers, likely lipid in nature, would be crucial to allow us to monitor efficacy of combinatorial therapies targeting lipid metabolism.