. Reduced pCREB in Alzheimer's disease prefrontal cortex is reflected in peripheral blood mononuclear cells. Mol Psychiatry. 2016 Sep;21(9):1158-66. Epub 2016 Aug 2 PubMed.


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  1. Professors Lazarov and Bennett have analyzed data from normal, MCI, and AD human samples, to create a novel and exciting hypothesis that may yield a desperately needed, non-invasive, translational biomarker for AD. They hypothesize that in AD, levels of the activated transcription factor pCREB are significantly lowered in both prefrontal cortex (PFC) and in peripheral blood mononuclear cells (PBMC). We hope that testing this peripheral biomarker hypothesis in longitudinal studies on a larger population of AD patients will lead to its use in translational studies. A similar correlation was not observed in MCI. In addition to pCREB, in the PFC of AD brains the researchers observed significant lowering of histone acetyl transferases (HATs), CBP, and p300, providing a fascinating, mechanistic link with pCREB and dysfunctional CREB-mediated transcription in AD, which had been explored in the earlier paper from Lazarov’s group (Bartolotti et al., 2015). 

    As outlined in their 2015 paper, Bartolotti et al. attempted to characterize the role of CREB activation and CRE-mediated transcription in cognitive impairment in the APPswe/PS1Δe9 FAD mouse. In young (three-month-old) FAD mice relative to wild-type, hippocampal pCREB, CREB, p300, and CBP levels and pCREB/CREB ratio were significantly lower. Protein immunoassay and additional experiments using a CRE-reporter immediately after behavioral testing, or after one week in an enriched environment, support the hypothesis that hippocampal CREB activation is functionally attenuated in FAD mice, resulting in impaired transcription of long-term memory related immediate early genes such as Egr-1. With this new work, Lazarov and colleagues further support a central role for dysfunctional CREB signaling in synaptic dysfunction in AD and suggest that this mechanism is not dependent on Aβ. Therapeutic approaches to CREB dysfunction in AD have been reviewed recently, including activation of HATs, and upstream targets (Ben Aissa et al., 2016; Teich et al., 2015). Limited exploration of upstream mediators was reported in the 2015 Bartolotti study, including canonical cAMP-dependent signaling via PKA. Notably, activation of the canonical pathway by rolipram has been shown previously to restore cognitive function in FAD mice (Gong et al., 2004). Similarly, both the Thatcher and Arancio groups have shown that activation of hippocampal pCREB via the non-canonical NO/GMP pathway (Lu et al., 1999) restores cognition in multiple FAD mouse models (Luo et al., 2015; Luo et al., 2016; Puzzo et al., 2009). Interestingly, in these studies targeting cGMP-dependent activation led to Aβ clearance, whereas targeting cAMP (Gong et al., 2004) and other pathways converging on pCREB (Fa et al., 2015; Trinchese, et al., 2008) appeared to be Aβ-independent. This highlights an intriguing discussion in the Lazarov papers, that cognitive loss, linked to CREB dysfunction, may be independent of Aβ in early AD; and encourages further studies in animal models not driven by Aβ.     

    In summary, the two papers from Lazarov and co-workers further support the critical role of CREB signaling in AD-related memory decline and therapeutic targeting of enhanced CREB activation. Most importantly, the study of human samples provides hope that a peripheral, translational biomarker is on the horizon, which will not only monitor early disease progression, but also strongly support the progress of therapeutic agents targeting CREB activation, such as NMZ (Luo et al., 2015; Luo et al., 2016), through clinical trials for Alzheimer’s disease. 


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