8 August 2006. Mounting evidence from mouse models points to soluble amyloid-β (Aβ) oligomers as the cause of early, reversible deficits in synapse function and memory (see ARF related news story and Walsh and Selkoe, 2004). But while preventing early synapse toxicity is a prime goal for therapeutic intervention in AD, little is known about what happens on the molecular level when healthy neurons first meet Aβ oligomers.
A possible route from Aβ to synaptic dysfunction that goes via N-methyl-D-aspartate (NMDA) receptors is outlined in a new paper from Brent Kelly and Adriana Ferreira from Northwestern University, Chicago, Illinois. Writing in the Journal of Biological Chemistry, they propose that Aβ oligomers (but not fibrils) cause calcium influx through NMDA receptors, which leads to activation of the calcium-dependent protease calpain and degradation of the synaptic vesicle protein dynamin. Dynamin is required for synaptic vesicle recycling, and its loss causes depletion of the vesicle pool and failure of neurotransmitter release. The results raise the possibility that dynamin depletion could contribute to synaptic dysfunction in AD and that calpain might present a potential target to prevent early synaptic changes.
In previous work, Kelly and Ferreira demonstrated that dynamin is proteolytically cleaved when cultured hippocampal neurons are exposed to Aβ oligomers (Kelly et al., 2005). The new work shows that the agent of dynamin’s destruction is the calcium-activated protease calpain. Exposure of neurons to aggregated Aβ for 24 hours caused calpain activation, and a specific calpain activator blocked dynamin cleavage under the same conditions. Activation of calpain and dynamin cleavage were both stimulated by soluble oligomeric Aβ, but not fibrillar Aβ.
The soluble Aβ species appeared to cause calpain activation by eliciting a rapid rise and prolonged elevation in intracellular calcium concentrations. The calcium originated from the extracellular pool, because the calcium increase could be blocked by external chelation with 1,2-bis (o-aminophenoxy) ethane-N,N,N’,N’-tetraacetic acid (BAPTA). Preventing calcium influx with BAPTA also inhibited calpain activation and dynamin cleavage, and reduced the appearance of neurite varicosities, morphological signs of neuron distress.
To figure out how calcium was getting into the cell, the researchers used specific inhibitors of several membrane calcium channels, showing that NMDA channels were most likely the source. Either MK801 or memantine—NMDAR antagonists—blocked dynamin cleavage, calpain activation, and early morphological changes in the cells. Neither the L-type voltage-gated calcium channel blocker nimodipine nor the sodium channel inhibitor TTX had any effect. The implication of NMDA receptors in Aβ toxicity is interesting based on recent reports that showed a decrease in surface levels of these protein receptors in response to Aβ (see ARF related news story). Perhaps, as Kelly and Ferreira speculate, the decrease could be the cells’ attempt to compensate for chronic receptor activation and elevated calcium.
While the responses of cultured hippocampal neurons may or may not reflect what happens in AD brain, both abnormal activation of the calpain system and loss of dynamin have been observed in brain tissue from AD patients (Saito et al., 1993; Liu et al., 2005; Yao et al., 2003). But whether these are important early events in disease remains to be investigated. Equally intriguing is the question of how Aβ oligomers might activate calcium influx via NMDA receptors. Do they bind directly to the receptor? Or will other mediators turn up?—Pat McCaffrey.
Kelly BL, Ferreira A. β-amyloid-induced dynamin 1 degradation is mediated by NMDA receptors in hippocampal neurons. J Biol Chem. 2006 Jul 24; [Epub ahead of print].