Fasudil, a chemical inhibitor used to treat strokes, may prevent early nerve cell impairment and sustainment of beta-amyloid damaging effects, opening new therapeutic avenues for Alzheimer’s disease, according to a mouse study.
These findings could not only help researchers understand the mechanisms behind Alzheimer’s development and progression, but also may shed light on why some therapies have failed in clinical trials.
The study, “A role for APP in Wnt signalling links synapse loss with β-amyloid production,” was published in Translational Psychiatry.
“Our work uncovers the intimate link between synapse [nerve cell communication] loss and beta-amyloid in the earliest stages of Alzheimer’s disease,” Christina Elliott, PhD, a researcher at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and the study’s lead author, said in a press release. “This is a major step forward in our understanding of the disease and highlights the importance of early therapeutic intervention.”
Overproduction of the beta-amyloid protein is linked to development of Alzheimer’s disease. Beta-amyloid attacks and destroys synapses — the junctions between two nerve cells that allow them to communicate — but many therapies targeting beta-amyloid have failed in clinical trials.
A protein called the amyloid precursor protein (APP), which gives rise to beta-amyloid, is known to play a central role in the development of Alzheimer’s disease and other progressive neurological conditions. However, the detailed mechanisms of its function and how it contributes to the formation of beta-amyloid toxic aggregates is still poorly understood.
Researchers at King’s College London modified laboratory cell lines to produce increased amounts of APP, finding that the protein activates two molecular pathways known to have opposing effects: the Wnt-β-catenin signaling pathway and the Wnt-planar cell polarity (Wnt-PCP) pathway. Under normal conditions, these two pathways are in tight balance to regulate nerve cell communication.
The team then used a mutated form of APP that has been associated with familial Alzheimer’s disease, also known as the Swedish mutation.
Compared with its normal version, mutated APP was found to effectively activate the Wnt-PCP pathway rather than the Wnt-β-catenin pathway, antagonizing its effects.
Of particular importance, researchers observed that the production of beta-amyloid molecules is associated with the activation of this same Wnt-PCP pathway, and is blocked by the Wnt-β-catenin pathway.
“We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production,” said the study’s senior author, Richard Killick. “We think that once this feedback loop gets out of control it is too late for drugs which target beta-amyloid to be effective, and this could explain why so many Alzheimer’s drug trials have failed.”
Researchers used a chemical inhibitor called fasudil that could prevent the activity of the Wnt-PCP pathway.
Fasudil has been approved in Japan and China as a vasodilator for the treatment of strokes and cerebral vasospasm. Several studies have suggested it could also prevent memory loss and treat several neurodegenerative disorders.
In a mouse model of Alzheimer’s disease, treatment with fasudil significantly protected the mice from beta-amyloid-mediated loss of nerve cell connectivity and cognitive impairment. In addition, the levels of free beta-amyloid and amyloid aggregates in the brain were substantially reduced upon treatment.
“Importantly, our work has shown that we may already be in a position to block the feedback loop,” Killick said. “We have convincingly shown that fasudil can protect synapses and memory in animal models of Alzheimer’s, and at the same time reduces the amount of beta-amyloid in the brain.”
These results demonstrate that “a central component of Alzheimer’s disease” development is the activity of APP “rather than beta-amyloid production per se,” the researchers wrote in the study.
“As well as being a safe drug, fasudil appears to enter the brain in sufficient quantity to potentially be an effective treatment against beta-amyloid,” said Dag Aarsland, MD, PhD, who is the chair of Old Age Psychiatry at IoPPN.
The team is currently seeking funding to conduct a trial in early-stage Alzheimer’s patients to determine if fasudil improves brain health and prevents cognitive decline.