. PPARγ recruitment to active ERK during memory consolidation is required for Alzheimer's disease-related cognitive enhancement. J Neurosci. 2014 Mar 12;34(11):4054-63. PubMed.


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  1. These findings are very interesting and have added to the growing body of evidence linking metabolic disease syndromes to cognitive dysfunction. The authors highlight and propose that the association between a phosphorylated form of ERK kinase and PPARγ potentially serves as a key molecular mechanism underlying the beneficial effects of insulin sensitizers (PPARγ agonists) on AD models.

    It would be too early to suggest phospho-ERK/PPARγ binding as a new therapeutic target for AD.  More functional, systematic studies need to be done to establish how specific this type of binding is to the pathophysiology of AD and other dementias. Meanwhile, it is noteworthy that the data reported in this paper revealed a nice correlation of phospho-ERK/PPARγ ratio and score on the MMSE (mini-mental state examination), a commonly used test in medicine to evaluate dementia and cognitive impairments. Thus, one may wonder whether the findings may be meaningful for development of certain biomarkers for dementia screening.

    I think it would be important to understand the molecular mechanisms downstream of phospho-ERK/PPARγ binding—especially because both ERK and PPARγ are well-known to be involved in gene expression, which is essential for maintaining long-term synaptic plasticity and memory (Klann and Dever, 2004). Indeed, we recently demonstrated that normalizing protein-synthesis defects in an AD model mouse by targeting the mRNA translational factor eIF2α prevents AD-associated plasticity failure and memory impairments (Ma et al., 2013). In short, it would be exciting for the authors or other investigators to further explore signaling mechanisms as well as functional consequences of insulin sensitizers in AD and other neurodegenerative diseases.    


    . Biochemical mechanisms for translational regulation in synaptic plasticity. Nat Rev Neurosci. 2004 Dec;5(12):931-42. PubMed.

    . Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat Neurosci. 2013 Sep;16(9):1299-305. PubMed.

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