The episodic hippocampal-dependent memory loss that occurs in the early stages of Alzheimer’s disease may be due to changes in synaptic function. Previous in vitro work indicated a link between synaptic failure and activity of caspase-3, a protease best known for its role in apoptosis. D’Amelio et al. found that Tg2576 transgenic mice (which express the human APPswe mutant allele associated with familial Alzheimer’s disease) showed deficits in hippocampal-dependent memory at 3 months of age, before the deposition of amyloid plaque, as well as reductions in spine density in apical dendrites, spine head diameter, and overall dendrite length. One mechanism underlying β-amyloid (Aβ)–induced losses in synaptic density is endocytosis of AMPA receptors, a process that requires the phosphatase calcineurin. The abundance of the AMPA receptor subunit GluR1, both total and phosphorylated at Ser845, was reduced in extracts of postsynaptic densities from Tg2576 mice but not in total hippocampal homogenates, which suggests redistribution of phosphorylated and total GluR1. Changes in GluR1 distribution in Tg2576 mice were blocked by hippocampal injection of a γ-secretase inhibitor to block production of Aβ. Electrophysiological experiments suggested increased long-term depression (which is associated with dephosphorylation of GluR1 at Ser845) in Tg2576 mice compared with wild-type mice. Tg2576 mice showed higher procaspase-3 abundance and caspase-3 activity in hippocampal homogenates and synaptosomes (as indicated by immunoblotting) and increased immunostaining for caspase-3 in postsynaptic densities. However, the increase in caspase-3 activity was not accompanied by enhanced neuronal apoptosis. Application of z-DEVD-fmk to Tg2576 hippocampal slices to inhibit caspase-3 activity increased the abundance of GluR1 and GluR1-phospho-Ser845 in postsynaptic density preparations. Treatment with z-DEVD-fmk decreased calcineurin activity in Tg2576 hippocampal slices, whereas calcineurin activity and processing were increased in 3-month-old Tg2576 mice. Injection of z-DEVD-fmk into the hippocampi of Tg2576 mice reduced caspase-3 activity and calcineurin processing, increased the abundance of GluR1 in postsynaptic density preparations and head diameter of dendritic spines, and improved memory deficits. In the accompanying Perspective, Hyman discusses the implications of this research for the development of new therapies for Alzheimer’s disease.
M. D'Amelio, V. Cavallucci, S. Middei, C. Marchetti, S. Pacioni, A. Ferri, A. Diamantini, D. De Zio, P. Carrara, L. Battistini, S. Moreno, A. Bacci, M. Ammassari-Teule, H. Marie, F. Cecconi, Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat. Neurosci. 14, 69–76 (2011). [PubMed]
B. T. Hyman, Caspase activation without apoptosis: Insight into Aβ initiation of neurodegeneration. Nat. Neurosci. 14, 5–6 (2011). [PubMed]