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.

Reference:
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

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  1. We recently witnessed the discovery of many Aβ receptors, but the exact signaling pathway through which Aβ (oligomers) mediated synaptic dysfunction (inhibition of LTP) is still not identified. This paper elegantly demonstrates the involvement of a signaling pathway that involves caspases, Akt1, and GSK-3β.

    Taking last year’s discovery on the involvement of caspases and LTD from Morgan Sheng’s lab (Li et al., 2010), the authors explored whether caspases could be involved in Aβ-induced LTP deficits. Indeed, Aβ induced LTP inhibition-required caspase-3 and/or caspase-7. These findings tie in nicely with the recent report that showed caspase-3 triggers early synaptic alterations in an AD mouse model (D’Amelio et al., 2011). Since Li et al. previously showed that caspase-mediated Akt1 cleavage is required for LTD, in the current study the authors studied whether caspase-3-mediated Akt1 cleavage was required for Aβ inhibition of LTP. By using mutants of Akt1 that are resistant to caspase cleavage, the authors quite nicely demonstrated that this is so. Following this line, the authors then investigated whether Akt inhibition-induced activation of GSK-3β is essential for this LTP inhibition, and sure enough, they find this to be the case as well.

    Overall, this study shows that the caspase-3/7-Akt inhibition-GSK-3β activation pathway is critically important for Aβ inhibition of LTP. There are many reasons why this study is quite important:

    1. It elucidates the signaling axis and hence also identifies therapeutic targets for AD: If Aβ has other physiological functions, then instead of inhibiting Aβ production, one could specifically target LTP effects by targeting one of these signaling players.

    2. This study again highlights a novel role of caspases outside their “apoptosis” role.

    3. Akt1 and GSK-3β, two kinases that have been previously implicated in tau phosphorylation, now are identified as key signaling proteins for LTP inhibition! In a recent RNAi-based screen for Aβ production, we identified both Akt1 and Akt2 as players involved in APP processing (Bali et al., 2011, under revision).

    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. These results show that there are feedback loops and that particular kinases (such as Akt1) can participate in the production of Aβ, tau phosphorylation, and in synaptic dysfunction, introducing complexity in the amyloid cascade. I find this absolutely fascinating! What this tells us is that we have to view Alzheimer’s disease as a complex system and study its complexity.

    View all comments by Lawrence Rajendran
  2. This study nicely examines potential signaling activated by β amyloid that could perturb LTP. The signaling identified can play multiple roles, so their exact participation in the effects of β amyloid needs to be elucidated. As targets for Alzheimer's disease, therapy is complicated by the fact that these signaling molecules participate in important physiological processes.

    View all comments by Roberto Malinow

References

News Citations

  1. Cutting Both Ways—Besides Death, Caspases Mediate Neurons' LTD
  2. Synaptic Plasticity, APP Processing—GSK3β Does It All
  3. Neuronal Glutamate Fuels Aβ-induced LTD
  4. Tau’s Synaptic Hats: Regulating Activity, Disrupting Communication

Paper Citations

  1. . Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell. 2010 May 28;141(5):859-71. PubMed.
  2. . LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron. 2007 Mar 1;53(5):703-17. PubMed.
  3. . Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. PubMed.
  4. . Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron. 2010 Dec 22;68(6):1067-81. PubMed.
  5. . Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci. 2011 Jan 12;31(2):700-11. PubMed.
  6. . Caspase-2 mediates neuronal cell death induced by beta-amyloid. J Neurosci. 2000 Feb 15;20(4):1386-92. PubMed.
  7. . Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci. 2011 May;14(5):545-7. PubMed.

Further Reading

Papers

  1. . Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci. 2011 May;14(5):545-7. PubMed.
  2. . Caspase activation precedes and leads to tangles. Nature. 2010 Apr 22;464(7292):1201-4. PubMed.
  3. . Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. PubMed.
  4. . Chronic lithium treatment decreases tau lesions by promoting ubiquitination in a mouse model of tauopathies. Acta Neuropathol. 2005 Dec;110(6):547-56. PubMed.
  5. . Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A. 2005 May 10;102(19):6990-5. PubMed.

Primary Papers

  1. . Aβ(1-42) inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci. 2011 May;14(5):545-7. PubMed.