“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