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Cruchaga C, Kauwe JS, Mayo K, Spiegel N, Bertelsen S, Nowotny P, Shah AR, Abraham R, Hollingworth P, Harold D, Owen MM, Williams J, Lovestone S, Peskind ER, Li G, Leverenz JB, Galasko D, , Morris JC, Fagan AM, Holtzman DM, Goate AM. SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer's disease. PLoS Genet. 2010 Sep;6(9) PubMed.
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This is a very interesting paper from Allison Goate and coworkers, who push genotype-phenotype analyses to the next level—towards understanding how variations in biomarkers relate to risk of progression of disease. A specific allele of calcineurin B, one of the subunits of calcineurin, is associated with rate of progression, phospho-tau levels, and tangle numbers. This is a tour de force of genotype-phenotype correlations and begins to potentially explore the wide variability in disease progression observed clinically. Of importance, age of onset travels not with calcineurin B, but with amyloid-related markers.
Calcineurin activation has been implicated by Paul Greengard and colleagues, Roberto Malinow’s laboratory, as well as multiple others, as being critical for expression of amyloid-β synaptotoxicity. Recent data from our laboratory, and from Chris Norris and colleagues, demonstrated elevated calcineurin activity in neurons and in glia in AD models and in AD brain, in part due to post-translational changes that lead to a constitutively active form. How this relates to the new genetic findings, and to tau phosphorylation, is not yet clear—and raises new questions about how regulation of calcineurin at the mRNA level relates to activity in the AD brain. Nonetheless, the link of biochemical and genetic data both focusing on calcineurin pathways is intriguing, and serves to highlight the potential importance of this central signaling pathway in AD pathophysiology.
University of Kentucky College of Medicine
This elegant manuscript by Cruchaga et al. reveals that CSF phospho-tau levels and the rate of disease progression in AD subjects are strongly correlated to the presence of SNPs in the regulatory B subunit of calcineurin, a Ca2+/calmodulin-dependent protein phosphatase implicated in several peripheral and neurologic disorders. These important observations could help establish a novel diagnostic marker in the clinic and lead to the development of treatments tailored to specific patient subpopulations.
At the same time, caution may be warranted in regard to the functional impact of these SNPs on calcineurin function in AD. The authors suggest that calcineurin B SNPs “reduce calcineurin expression/activity leading to an increase in tau phosphorylation, tau pathology and neurodegeneration in individuals with Aβ deposition.” This conclusion was based on two primary pieces of evidence: First, that calcineurin inhibitors increase tau phosphorylation in mice (1,3) and second, that calcineurin activity is reduced in Alzheimer’s disease brain (4). However, numerous recent findings seem inconsistent with a “reduced calcineurin” hypothesis. In particular, calcineurin inhibitors (or inhibitors of the calcineurin-dependent transcription factor NFAT) typically provide strong protection against synaptic dysfunction (5,6), dendritic atrophy/spine retraction (7-9), neuroinflammation (10,11), amyloid pathology (12,13), neuronal death (14,15), and cognitive decline (16) in a variety of cell culture and/or animal models of AD.
Moreover, recent studies using alternative antibodies and assays have observed hyperactive, rather than hypoactive, calcineurin signaling in AD mice and in subjects with MCI or AD (8,16-19). The work performed on postmortem human tissue suggests that AD-mediated changes in calcineurin signaling are very complex and depend on a number of factors including: the brain region, cell type (neurons vs glia), and calcineurin isoform (alpha vs beta) investigated; the proteolytic state and subcellular localization of the calcineurin catalytic subunit (i.e. the A subunit); and the pathologic and cognitive status of the subject. Clearly, it will be important to determine how SNPs in the regulatory calcineurin B subunit affect these calcineurin A signaling properties.
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