5 April 2011. Indications are that amyloid-β destroys memory by disrupting synaptic plasticity. A Nature Neuroscience paper posted online March 27 lays out three possible steps along the way. “Amyloid-β activates caspases; this cleaves Akt1, which normally inhibits GSK-3β,” concluded senior author Kwanwook Cho of the University of Bristol, U.K., in an e-mail to ARF. These participants, then, could be drug targets for scientists hoping to protect memory.
Joint first authors Jihoon Jo and Daniel Whitcomb led the study. They used hippocampal slice cultures, and treated them with synthetic amyloid-β1-42 mostly in the dimer to hexamer size range. The neurons evinced long-term potentiation (LTP) only in the absence of Aβ. Given past results fingering caspases as key to long-term depression (LTD; see ARF related news story on Li et al., 2010), the researchers tested whether caspase inhibitors would affect amyloid-β’s effect on LTP. Indeed, in the presence of broad-spectrum caspase blockers, Aβ treatment did not dampen LTP in the slices. When the scientists used more specific inhibitors, they found that caspase-3 activity was important for Aβ-induced depression of LTP. They also confirmed that in slices from caspase-3 knockout mice, Aβ did not affect LTP in hippocampal slices.
Since caspase-3 cleaves Akt1, the researchers examined the role of this kinase in their slices. When they transfected cells with a mutant, cleavage-resistant form of Akt1, amyloid-β was unable to block LTP. Thus, caspase-3 must cleave Akt1 in order to slow LTP. Akt1 inhibits GSK-3β (glycogen synthase kinase-3β), which promotes LTD but is itself inhibited by LTP (see ARF related news story on Peineau et al., 2007). In the slices, inhibiting GSK-3β prevented amyloid-β from blocking LTP.
The question remains as to what connects amyloid-β and caspase-3. The caspase might be responding to altered mitochondrial function and calcium regulation, Cho suggested. Other researchers have found evidence for glutamate signaling (see ARF related news story on Li et al., 2009), mutant tau, and the kinase Fyn (see ARF related news story on Hoover et al., 2010 and Roberson et al., 2011) as mediators of Aβ synaptic effects.
The work has implications for the study of Aβ in general, wrote Lawrence Rajendran of the University of Zurich in Switzerland in an e-mail to ARF. Akt1 and GSK-3β both phosphorylate tau, and Akt1 is involved in APP processing, he noted. “All of these data suggest that the way Aβ elicits neurodegeneration might not be as linear and unidirectional as proposed by the amyloid cascade hypothesis,” he wrote. “There are feedback loops…a particular kinase (such as Akt1) could participate in the production of amyloid-β, tau phosphorylation, and in synaptic dysfunction, introducing complexity in the amyloid cascade.”
The work suggests that targeting caspases, Akt1 or GSK-3β could be a way to rescue cognition in Alzheimer’s disease. However, “therapy is complicated by the fact that these signaling molecules participate in important physiological processes,” commented Roberto Malinow of the University of California in San Diego, in an e-mail to ARF.
“This is a very nice, consistent story with very good LTP data,” said Michael Shelanski of Columbia University in New York, who was not involved in the work. However, he confessed himself “befuddled” at how some studies point to caspase-3 as key in amyloid-β pathology, while his lab has found that caspase-2 is most crucial in mediating synaptic structure, cognition, and cell death in the presence of amyloid-β (Troy et al., 2000 and Pozueta et al., submitted).—Amber Dance.
Jo H, Whitcomb DJ, Olsen KM, Kerrigan TL, Lo SC, Bru-Mercier G, Dickinson B, Scullion S, Sheng M, Collingridge G, Cho K. Abeta(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3beta. Nat Neurosci. 2011 Mar 27. Abstract