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Müller M, Cárdenas C, Mei L, Cheung KH, Foskett JK. Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13293-8. PubMed.
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Rosalind Franklin University/The Chicago Medical School
The prominence of early/pre-symptomatic calcium signaling disruptions in mutant presenilin (PS)-expressing neurons has been well established in the AD field, but to fortify relevance to the disease process, dysregulated calcium still needs to be transduced into a pathogenic mechanism. This study by Müller et al. is very effective at demonstrating how increased ER calcium release, via the IP3R, results in constitutive upregulation of a calcium-regulated kinase and gene transcription pathway.
Normally, CaMKIV and pCREB activation are associated with neuronal functionality and plasticity, and are recruited in a specific and activity-dependent manner. However, with mutant PS expression, this signaling cascade and associated immediate early genes are continuously engaged. While there are many long-term negative effects that can stem from this homeostasis shift (such as the demonstrated increased vulnerability to cell death and amyloid toxicity), the specific links to AD pathology are still to be determined.
We know that at early disease stages, prior to the onset of amyloid pathology or cognitive impairment, these neurons "appear" normal from an electrophysiological and synaptic transmission standpoint, despite a "below the radar" shift in calcium release and intracellular signaling homeostasis. It is likely that sustained dyshomeostasis of normally functional pathways can ultimately contribute to dysfunctional outcomes.
Studies such as these stress the importance of investigating early pathogenic mechanisms in AD. By targeting proximal and reversible aberrant signaling cascades, these approaches will likely provide the greatest opportunity for generating preventative or disease-altering therapeutics.
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