In AD therapy, it may be time for an alternative target to shine: the α7 nicotinic acetylcholine receptor. Earlier this week, scientists at the Alzheimer’s Association International Conference (AAIC), held 14-19 July 2012 in Vancouver, Canada, reported that an α7 receptor agonist met its clinical endpoints in a Phase 2 AD trial (see ARF related news story). Now comes a July 18 Journal of Neuroscience paper that describes a novel approach for targeting the receptor. Researchers led by Hoau-Yan Wang at the City University of New York and Lindsay Burns at Pain Therapeutics, Inc., Austin, Texas, report that a preclinical compound, PTI-125, interferes with Aβ42’s toxic signaling by reducing the peptide’s affinity for the α7 receptor. In a mouse model, the drug reduced amyloid deposits, tau phosphorylation, and inflammation, and normalized signaling through the α7 receptor as well as NMDA and insulin receptors, the authors report. “This compound seems to affect all the major pathogenic pathways,” Wang told Alzforum, adding that the company is moving forward with preclinical work and safety studies. Wang consults for Pain Therapeutics.

“It is a novel therapeutic approach and potentially promising,” said Marwan Sabbagh at Banner Sun Health Research Institute in Sun City, Arizona, though he noted that the results are preliminary and need repeating. “It refocuses attention on the α7 nicotinic receptor as a therapeutic target.” Sabbagh was not involved in the work.

Aβ binds to α7 receptors with high affinity, kicking off synaptic deficits and memory problems (see ARF related news story; Liu et al., 2001; and Pettit et al., 2001). Previous work by Wang’s group showed that this interaction also stimulates tau phosphorylation (see ARF related news story on Wang et al., 2003) and Aβ42 internalization and deposit formation (see ARF related news story on Wang et al., 2009; Nagele et al., 2002), although other groups have not yet repeated all of these results.

In the current paper, Wang and colleagues tested whether Pain Therapeutics’ compound PTI-125 could reverse these effects. Why the researchers expected it to is not clear. The researchers first infused a solution of monomeric and oligomeric human synthetic Aβ42 into the cerebral ventricles of wild-type mice for seven days, resulting in high levels of Aβ bound to the α7 receptor in the hippocampus and prefrontal cortex. When the Aβ-infused animals were injected intraperitoneally twice daily with 10 mg/kg PTI-125 during the same period, however, the amount of Aβ42 bound to the nicotinic receptor dropped by two-thirds or more. How does the drug knock Aβ off the receptor? Indirectly, the authors suggest. In Aβ-infused mice, the amount of the scaffolding protein filamin A bound to the α7 receptor jumped dramatically compared to levels in control mice. After PTI-125 treatment, filamin A levels at the receptor fell back to normal. Filamin A may stabilize the interaction of Aβ with the α7 receptor, the authors propose. In the absence of the scaffolding protein, the affinity of the peptide for the receptor plummets.

In keeping with this idea, the authors report numerous beneficial effects of PTI-125 treatment on Aβ pathology. Tau phosphorylation dropped and β amyloid deposits shrank in treated mice. The authors speculate that deposits cleared up because Aβ was no longer binding α7 and being internalized. Calcium influx through the nicotinic receptor normalized. Signaling through the NMDA and insulin receptors also improved, as shown by increased recruitment of downstream signaling components to these receptors in treated mice. Levels of inflammatory cytokines dropped, which the authors trace to lower binding of filamin A and Aβ42 to toll-like receptor 4, a mediator of inflammation. They suggest that the improvement in insulin signaling may be a secondary effect of lowered inflammation, but have not tested this idea.

To extend the results to humans, the authors turned to postmortem brains donated by people with AD and healthy age-matched controls. They used portions of the frontal cortex, which were collected within a few hours after death, snap frozen, and then thawed gradually so as not to shock the tissue, Wang told Alzforum. Like the Aβ-infused mice, AD brains showed elevated levels of filamin A bound to the α7 nicotinic receptor. Incubation of brain slices with PTI-125 reversed this association, and also reduced the amount of Aβ42 bound to the receptor. This implies that the drug can knock off bound Aβ even in late-stage disease, the authors suggest. Synaptosomes prepared from AD brain tissue showed lower calcium influx after stimulation compared to control tissue, but the drug normalized calcium uptake. NMDA and insulin receptor function also improved upon treatment, as they did in mice.

One advantage of this therapeutic approach is that it does not interfere with physiological cholinergic signaling, and therefore should have few side effects, the authors point out. Wang noted that preliminary toxicity tests look good. He plans to continue with safety studies and also examine other animal models. Ben Thornton, senior vice president at Pain Therapeutics, wrote to Alzforum that the company is looking for a partner to help take this work forward.

Sabbagh finds it intriguing that Aβ can act as a receptor ligand. “That is quite an innovative idea,” he said. The data also provide a mechanistic link between Aβ activity and tau phosphorylation, he noted. Other work has shown a connection between Aβ toxicity and tau localization (see ARF related news story; ARF news story). Sabbagh pointed out, however, that nicotinic receptor properties can vary greatly from one mouse model to another, and mouse tau is quite different from human tau. “It will be imperative to try [these experiments] in more than one mouse model, and then move up to higher-order animals,” he said. He also noted the importance of looking at long-term potentiation and cognition in treated mice to see if they improve in these measures as well.

Gerhard Koenig at Envivo Pharmaceuticals, Watertown, Massachusetts, told Alzforum that these interesting findings might partly explain Aβ42 toxicity. However, he noted that co-immunoprecipitations, which the authors use to show reduced or increased receptor binding, are generally only semi-quantitative. “It will be interesting to see parts of these findings extended into some in-vivo efficacy studies,” he wrote to Alzforum (see full comment below).—Madolyn Bowman Rogers.

Reference:
Wang HY, Bakshi K, Frankfurt M, Stucky A, Goberdhan M, Shah SM, Burns LH. Reducing amyloid-related Alzheimer’s disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. Abstract

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  1. This is an interesting paper and follows the initial findings of Wang et al., 2000 (same first author), where it was shown that Aβ42 has a very high-affinity interaction with the α7 nicotinic acetylcholine receptor. The intracerebrovascular infusion of Aβ42 into mice that induced certain tau-phospho-epitopes and was blocked by the small molecule PTI-125 is intriguing. This compound works at the nanomolar range, which is very potent, by preventing binding of the scaffolding protein, filamin A (FLNA), to the nicotinic receptor.

    The authors claim in Table 1 that they have been able to stimulate the FLNA/receptor interaction with several α7-specific ligands (methyllycaconitine, aBgTx, PNU282987). However, all three of these agents are potent α7 binders (24 nM for PNU and single-digit nanomolar for the other two). It would have been good if they had used lower doses (say, 10-fold over Ki but not 250- to 1,000-fold over Ki) for these compounds. The α7 agents that have been used clinically and have shown promise typically act in the concentrations that are closer to the Ki; that is, functional assays typically overestimate the concentrations needed to predict animal and/or human efficacy. This is important because one wants to know whether the agonists act as functional antagonists if used at these higher doses in a chronic manner, or whether it is true functional agonism. If the α7 agonists work only at these higher concentrations, the implications for their clinical use are not immediately apparent. Of course, that is different if one focuses on compounds with similar mechanisms of actions as PTI-125.

    Furthermore, the method of co-immunoprecipitation is at best semi-quantitative, but the authors based their quantitative pharmacological interpretation on these assays. The authors show also a functional impairment of α7 signaling through either Aβ infusion or from AD brains, which can be ameliorated by PTI-125. While they state in the discussion that PTI-125 is orally bioavailable in rats, they used it intraperitoneally. It would be nice to get concentration ranges for the PTI-125-treated animals to see how it relates to the in-vitro or ex-vivo experiments.

    Clearly, the authors went to great lengths to extend their earlier findings that the α7 receptor is a main conduit of Aβ42-mediated toxicity. It is a very dense paper, and it may explain Aβ42 toxicity and how that could be blocked or ameliorated by PTI-125. It will be interesting to see parts of these findings extended into in-vivo efficacy studies.

    References:

    . Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem. 2000 Sep;75(3):1155-61. PubMed.

References

News Citations

  1. Experimental α7 Agonist Meets Cognitive and Clinical Endpoints
  2. Nicotinic Knockouts Reveal Role of Aβ Receptor in AD Mice
  3. Nicotine and β Amyloid—Smoking Guns?
  4. Reelin, Aβ, α7 Play Yin and Yang Around NMDA Receptors
  5. Honolulu: The Missing Link? Tau Mediates Aβ Toxicity at Synapse
  6. The Plot Thickens: The Complicated Relationship of Tau and Aβ

Paper Citations

  1. . beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4734-9. PubMed.
  2. . beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J Neurosci. 2001 Jan 1;21(1):RC120. PubMed.
  3. . Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem. 2003 Aug 22;278(34):31547-53. PubMed.
  4. . Dissociating beta-amyloid from alpha 7 nicotinic acetylcholine receptor by a novel therapeutic agent, S 24795, normalizes alpha 7 nicotinic acetylcholine and NMDA receptor function in Alzheimer's disease brain. J Neurosci. 2009 Sep 2;29(35):10961-73. PubMed.
  5. . Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease. Neuroscience. 2002;110(2):199-211. PubMed.
  6. . Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. PubMed.

Further Reading

Papers

  1. . Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. PubMed.

Primary Papers

  1. . Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A. J Neurosci. 2012 Jul 18;32(29):9773-84. PubMed.