10 September 2010. Amid the flood of reports on Aβ and tau, a steady trickle of studies is building the case for mismanaged neuronal calcium as a trigger of synaptic troubles that contribute to Alzheimer disease. In this week’s Journal of Neuroscience, Grace (Beth) Stutzmann, Rosalind Franklin University, North Chicago, Illinois, and colleagues report that calcium influx through NMDA-type glutamate receptors can unleash excess calcium from intracellular stores in neuronal dendrites of pre-symptomatic AD transgenic mice. Though past work had established that AD mice ramp up calcium flow through endoplasmic reticulum (ER) calcium channels well before pathology develops, the current study links that extra calcium with a physiologically relevant condition—synaptic stimulation.
Abnormal calcium signaling is believed to feed into AD pathogenesis in various ways. Recent reports propose that presenilins may function as ER calcium leak channels (Tu et al., 2006 and ARF related news story), interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) calcium release channel (Cheung et al., 2008 and ARF related news story), and/or activate sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) pump proteins (Green et al., 2008 and ARF related news story). Stutzmann’s lab has shown that hippocampal neurons from young triple-transgenic (3xTg AD) mice—which express mutant forms of presenilin-1, amyloid precursor protein (APP), and tau—exhibit normal synaptic plasticity and transmission despite having 10-15 times more calcium flowing out of ryanodine receptor-type (RyR) ER calcium channels (Chakroborty et al., 2009 and ARF related news story). In the current report, first author Ivan Goussakov and colleagues confirm those observations in another transgenic AD strain—the TASTPM mouse that expresses mutated APP and presenilin-1 (Howlett et al., 2004)—and show the effects can be produced using physiological triggers of calcium release.
For the latter, the researchers zapped layer V pyramidal neurons in cortical brain slices of young (four to six weeks old) AD mice with a 30 Hz stimulus and measured resulting calcium responses using electrophysiology and calcium imaging. The synaptic stimulation led to bigger calcium signals in cortical dendrites of both AD strains, compared with non-transgenic mice. Addition of an RyR agonist (caffeine) intensified the calcium response, whereas an antagonist (ryanodine at high doses) attenuated it, demonstrating that ryanodine receptors are responsible for the excess calcium release.
In another set of studies, Goussakov and colleagues were able to link the synaptically driven effects directly to NMDA receptor activity, but with a curious twist. They found that whole-cell NMDA electrical currents did not differ in neurons from non-transgenic and AD mice. However, upon NMDA receptor activation, dendritic synapses of both AD strains had stronger calcium responses than did those of non-transgenic neurons, and RyR inhibition brought the heightened calcium responses of AD neurons back to non-transgenic levels.
The data show, for the first time, “that calcium influx through NMDA receptors actually appears normal,” Stutzmann said. “However, it recruits a ryanodine-mediated calcium response that is very abnormal.” This suggests that calcium signals from NMDA receptors help trigger the extra influx of calcium through ryanodine channels in synapse-rich regions of AD neurons. “That might be sufficient, over time, to generate the more profound synaptic pathology,” Stutzmann said. The crosstalk with ryanodine receptors seemed specific to NMDA receptors, as calcium from voltage-gated stores did not similarly enhance calcium responses in AD neurons.
The new findings seem to challenge the prevailing view that NMDA receptors are the source of aberrant calcium signaling. That idea draws strength from recent work suggesting that toxic Aβ oligomers increase calcium influx through glutamate receptors (Shankar et al., 2007 and ARF related news story) and even metabotropic glutamate receptors (Renner et al., 2010 and ARF related news story). It may be hard to draw direct comparisons with the current paper, though, since Stutzmann and colleagues analyzed neurons of young AD mice with little to no detectable Aβ pathology.
Though the current studies were done using neurons from mice with familial AD (FAD) gene mutations, scientists think the findings could also be relevant to sporadic AD. Ilya Bezprozvanny, University of Texas Southwestern Medical Center, Dallas, noted that the increased calcium release in neurons with FAD-linked presenilin mutations resembles “what you would see in all aging neurons, but everything is more dramatic and much faster.” As such, the data “make the case that people with presenilin mutations may have big changes in their calcium signaling when they’re 40, for example, whereas people without the mutations may not have the changes until they’re 80,” Bezprozvanny said. Even among presenilin-1 mutation carriers, AD develops at various ages, and a recent study by Bezprozvanny’s lab suggests that the differential effects of various PS1 mutations on intracellular calcium signaling could underlie the onset age heterogeneity (Nelson et al., 2010).—Esther Landhuis.
Goussakov I, Miller MB, Stutzmann GE. NMDA-mediated Ca2+ influx drives aberrant ryanodine receptor activation in dendrites of young Alzheimer’s disease mice. J. Neurosci. 2010 Sep 8;30(36):12128-12137. Abstract