In a study at King’s College London, scientists have shown that a vicious circle in which the ill-famed amyloid-beta protein stimulates its own production might be a key factor in the etiology of neurodegeneration in Alzheimer’s disease; furthermore, a drug known as fasudil seems to be effective against amyloid-beta in a mice model of the disease [1].

Study abstract In Alzheimer’s disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by β-amyloid (Aβ) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-β-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aβ-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aβ production, while activation of canonical signalling suppresses Aβ production. Together, these findings identify a pathogenic-positive feedback loop in which Aβ induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aβ production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aβ production. Finally, we report that pharmacological inhibition of the Aβ-Dkk1-Aβ positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aβ load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aβ accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

The amyloid hypothesis

One of the most classical hypothesis on the etiology of Alzheimer’s disease is that the accumulation of an extracellular aggregate, the amyloid-beta protein, builds up in the patient’s brain, eventually reaching a level of abundance sufficient to disrupt neuronal communication. To date, countless clinical trials of drugs that interfere with amyloid-beta production have failed; in several of these cases, the drugs were unsuccessful at preventing or reversing cognitive decline despite being effective against amyloids themselves. These failures have led to new hypotheses being put forward, such as the tau and neurovascular hypotheses.

However, King’s College researchers think they have discovered a factor that might explain why the anti-amyloid drugs have failed.

A vicious circle







The researchers found out that, as amyloid-beta accumulates and destroys synapses—the structures connecting neurons to each other—they respond by producing yet more amyloid-beta, which, in turn, ends up causing the destruction of even more synapses, and so on. Eventually, the researchers suggest, this feedback loop gets to a point where it’s too late for drugs targeting amyloid-beta to be effective, which might explain the earlier failures.

In a previous paper [2] by the study’s senior author, Dr. Richard Killick, it was shown that a protein called Dkk1 is strongly associated with the pathology; in this study, the researchers found out that Dkk1, whose production ramps up with age, is key to the amyloid vicious circle. For this reason, the team believes that targeting Dkk1, rather than amyloids, might be a better therapeutic strategy.

The good news is, there already exists a safe, approved drug that is able to break the loop, at least in mice; the drug, known as fasudil, is already used in humans to treat stroke. In their study, the scientists showed that just two weeks of treatment with fasudil are sufficient to produce a significant reduction in amyloid-beta deposits.

Conclusion

According to Dr. Killick, fasudil can protect synapses and memory in animal models of Alzheimer’s, but it remains to be seen whether the drug will be equally successful in humans. Indeed, the researchers are now looking for funding to carry out a human trial; the trial would be run on early-stage Alzheimer’s patients with the aim of establishing whether administering fasudil can preserve brain health and prevent cognitive impairment.







Literature

[1] Elliott, C., Rojo, A. I., Ribe, E., Broadstock, M., Xia, W., Morin, P., … Killick, R. (2018). A role for APP in Wnt signalling links synapse loss with β-amyloid production. Translational Psychiatry, 8(1).

[2] Killick, R., Ribe, E. M., Al-Shawi, R., Malik, B., Hooper, C., Fernandes, C., … & Lin, K. (2014). Clusterin regulates β-amyloid toxicity via Dickkopf-1-driven induction of the wnt–PCP–JNK pathway. Molecular psychiatry, 19(1), 88.