At the Society for Neuroscience annual meeting held 17-21 October 2009 in Chicago, several posters beefed up the concept that signaling via calcineurin and nuclear factors of activated T cells (NFATs) may play a central role in neurodegenerative disease pathogenesis. One study puts forth calcineurin activation as a critical step linking soluble Aβ to downstream spine morphological changes in neurons. Other analyses reveal elevated levels of activated calcineurin in people with mild cognitive impairment (MCI), suggesting that this pathway starts to malfunction early in the disease course. And work from a third research group indicates that calcineurin may function similarly in Parkinson disease, mediating the neurotoxic effects of α-synuclein oligomers.
Using multiphoton imaging, Brad Hyman and colleagues at Massachusetts General Hospital, Charlestown, have reported dramatic changes in dendrites and dendritic spines in the vicinity of amyloid plaques in Tg2576 AD transgenic mice (Spires et al., 2005). Paul Greengard’s lab at Rockefeller University, New York, showed that interfering with extracellular signal-regulated kinase (ERK) or calcineurin pathways was sufficient to block Aβ-induced spine changes in vitro (Snyder et al., 2005). And more recent work led by Massachusetts General colleague Brian Bacskai demonstrated that Aβ plaques have even more far-reaching effects—namely, chronic elevations of resting calcium levels in surrounding astrocytes that spread as calcium waves across large distances (Kuchibhotla et al., 2009 and ARF related news story). Taken together, these findings “led to the plausible hypothesis that one of the things calcium does is activate calcineurin,” Hyman told ARF. “That would be a nice way to link Greengard’s observations in vitro with our observations in vivo.”
In their SfN poster, first author Haiyan Wu and colleagues showed that Aβ exposure led to dendritic spine changes, as well as activation and nuclear translocation of NFATc4, in cultured cortical neurons. They were able to block all these effects using calcineurin or NFAT inhibitors. “That suggests that calcineurin activation was a critical signaling mechanism that converts soluble Aβ to neuronal abnormality,” Hyman said. Furthermore, his team was able to phenocopy the Aβ-induced changes in wild-type neurons by transfecting them with a constitutively active form of calcineurin, showing that calcineurin is not only necessary but sufficient to mediate the Aβ effects.
Hyman and colleagues have some evidence to suggest these findings are relevant to AD. They found accumulation of NFATc4 and an active form of calcineurin in nuclear extracts from AD compared to control brain tissue.
This jibes with new data from Chris Norris’s lab at the University of Kentucky in Lexington. In a study published last month, first author Hafiz Abdul and colleagues found higher amounts of several activated NFATs in nuclear fractions of postmortem brain tissue from MCI and AD patients, relative to healthy seniors (Abdul et al., 2009 and ARF related news story).
At SfN, Abdul and colleagues presented a poster showing a corresponding increase in activation of calcineurin—the phosphatase that regulates NFAT activity—in the same MCI and AD samples. Previous work had demonstrated increases in calpain-mediated proteolysis and activation of calcineurin in severe AD (Liu et al., 2005), and the new data from Norris’s group suggest that these abnormalities begin in earlier stages of disease. Specifically, Abdul and colleagues found that MCI cytosolic fractions had higher levels of calpain-1 and the 45 kDa activated calcineurin-Aα fragment. Treatment with oligomeric Aβ was able to induce proteolysis of calcineurin to the 45 kDa fragment in mixed hippocampal cultures, and the calpain inhibitor calpeptin tempered this activity.
On another poster from the Norris lab, Jennifer Furman and colleagues reported looking at production of inflammatory cytokines, the downstream effect of NFAT-mediated signal transduction. They found that GM-CSF, TNFα, and IL-1β are upregulated in AD, and to some extent in brain samples from MCI and milder “preclinical” patients, too. (Patients were classified as control, MCI, or preclinical based on pathology and cognitive status as determined by the Mini-Mental State Examination. The control and preclinical groups had MMSE scores of 28-29, and MCI participants had scores around 24.) Levels of the three upregulated cytokines seemed to correlate with nuclear accumulation of NFAT1, but not NFATs 2 or 3. As reported on the poster, these findings suggest that “at least some components of neuroinflammation are increased in the very early stages of AD and are due, in part, to elevated NFAT1 activation.”
Last but not least, work by Giulio Taglialatela and colleagues at University of Texas Medical Branch, Galveston, suggests that the calcineurin/NFAT pathway may play a central role in Parkinson disease, too. Earlier, his group showed that oligomeric Aβ induces calcineurin activity and triggers downstream neurotoxic events in Tg2576 neurons (Reese et al., 2008). In their SfN poster, Taglialatela and colleagues show that oligomers of α-synuclein that are structurally similar to Aβ oligomers mediate similar calcineurin-dependent events in human neuroblastoma cells and mice. Furthermore, they report increased calcineurin activity in the brains of transgenic mice overexpressing mutant α-synuclein and in brain tissue from people with dementia with Lewy bodies (DLB), a dementia spectrum disorder that combines elements of AD and PD.—Esther Landhuis.