. Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. Ann Neurol. 2011 Feb;69(2):248-56. PubMed.


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  1. Despite the significant increase in our understanding of mechanisms that lead to neuronal damage and memory loss in Alzheimer’s disease (AD), to date there are no effective ways to prevent or treat this devastating disease. Thus, identifying and validating novel therapeutic targets in AD remain major research goals. In this paper just published in Annals of Neurology, Himeno and coworkers have investigated the effects of apomorphine (APO) on neuropathological alterations and memory impairment in 3xTg mice. APO is a non-specific dopamine receptor agonist, exhibiting submicromolar affinities for both D1-type and D2-type dopamine receptors. In addition to its dopaminergic action, APO has been shown to protect neurons from oxidative stress in experimental models of Parkinson’s disease and stroke. Because oxidative stress is a prominent feature in AD brains, Himeno et al. tested the hypothesis that APO might protect 3xTg mice from amyloid-induced brain pathology and memory deficits. In line with their expectations, they found that Tg mice treated for one month with weekly injections of APO exhibited significantly improved performance in memory tasks compared to untreated Tg animals. Interestingly, they also found that treatment with APO stimulates the degradation of Aβ by insulin-degrading enzyme (IDE), thus reducing neuronal levels of amyloid peptide. As an added bonus, neuronal levels of phosphorylated tau (p-tau), a hallmark of AD pathology, were also reduced in APO-treated Tg mice.

    Even though Himeno’s study suggests that neuroprotection by APO is largely due to its ability to block neuronal oxidative stress and reduce intraneuronal amyloid, there may be more to this story than first meets the eye. In a recently published study (Jurgensen et al., 2010), we showed that a specific D1-type dopamine receptor agonist blocked the removal of surface AMPA and NMDA receptors from synapses in cultured hippocampal neurons. Redistribution of AMPA and NMDA receptors from synapses is instigated by soluble Aβ oligomers, increasingly recognized as the proximal neurotoxins in AD, and is related to dephosphorylation of critical serine residues responsible for membrane insertion of the receptors. In the specific case of AMPA receptors, we showed that Aβ oligomers induce calcineurin-mediated dephosphorylation of Ser845 of the GluR1 subunit, causing the receptor to be removed from the membrane.

    Because AMPA and NMDA receptors play key roles in synaptic plasticity, our findings provide a direct molecular mechanism to explain the inhibition of synaptic long-term potentiation (LTP) and the facilitation of long-term depression (LTD) induced by Aβ oligomers. Directly supporting and extending these findings, a paper just out in Nature Neuroscience (D’Amelio et al., 2010) showed a calcineurin-dependent decrease in phosphorylation of GluR1 at Ser845, followed by removal of AMPA receptors from synapses in Tg2576-APPSwe mice. Interestingly, both Jurgensen et al. and D’Amelio et al. showed that neither AMPA nor NMDA receptors are readily degraded upon their removal from the surface, suggesting that mechanisms capable of stimulating reinsertion of the receptors into the neuronal membrane could potentially counteract the negative impact of Aβ oligomers. To test this hypothesis, we asked whether a specific D1-receptor agonist could rescue neurons from Aβ oligomer-induced loss of surface receptors and inhibition of plasticity. The rationale for this was that D1 receptors are coupled to stimulatory G proteins that activate adenylate cyclase, leading to increased production of cAMP. In turn, cAMP activates protein kinase A (PKA), which phosphorylates AMPA and NMDA receptors at the serine residues that control membrane insertion.

    Remarkably, we found that the D1 agonist effectively blocked dephosphorylation and removal of AMPA and NMDA receptors from the neuronal membrane, and prevented oligomer-induced inhibition of LTP in hippocampal slices. This suggests that specific activation of D1 dopamine receptors could be a novel therapeutic approach to prevent Aβ oligomer-induced synapse failure and memory loss in the early stages of AD.

    Thus, in addition to the possible antioxidant action and the ability to increase Aβ degradation (as suggested by Himeno’s study), direct neurochemical effects of dopamine receptor agonists may be beneficial in AD. From a therapeutic point of view, however, APO would probably not be the best choice. As mentioned above, APO is a non-specific dopamine receptor agonist, acting on both D1 and D2 families of receptors (in fact, APO has higher affinities for D2-like than for D1-like receptors). Contrary to D1-like receptors, D2-like receptors are coupled to inhibitory G proteins, thus leading to reduced cAMP production and reduced PKA-dependent phosphorylation of AMPA or NMDA receptor subunits. Moreover, because D2 receptors are particularly enriched in the nigrostriatal pathway involved in motor control, use of a drug that activates D2 receptors in this brain region may lead to undesirable, or perhaps unacceptable, side effects. Yet another side effect of APO, related to activation of D2 receptors, is that it is a potent emetic. On the other hand, D1 receptors are enriched in projections from the ventral tegmental area to the hippocampus, a circuitry that is known to play important roles in learning and memory.

    In conclusion, the possibility to combat synapse failure and memory loss by selective activation of D1 receptors should be further investigated as an approach to develop more effective treatments in AD.


    . Activation of D1/D5 dopamine receptors protects neurons from synapse dysfunction induced by amyloid-beta oligomers. J Biol Chem. 2011 Feb 4;286(5):3270-6. PubMed.

    . Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nat Neurosci. 2011 Jan;14(1):69-76. PubMed.

  2. Very nice studies of how a classic small molecule with action at numerous receptors could be therapeutic for AD.

This paper appears in the following:


  1. New Paths to Protect Synapses From Aβ?


  1. Intraneuronal Aβ: Was It APP All Along?