Discovery could explain failed clinical trials for Alzheimer's, and provide a solution

Researchers at King's College London have discovered a vicious feedback loop underlying brain degeneration in Alzheimer's disease which may explain why so many drug trials have failed. The study also identifies a clinically approved drug which breaks the vicious cycle and protects against memory-loss in animal models of Alzheimer's.

Overproduction of the protein beta-amyloid is strongly linked to development of Alzheimer's disease but many drugs targeting beta-amyloid have failed in clinical trials. Beta-amyloid attacks and destroys synapses - the connections between nerve cells in the brain - resulting in memory problems, dementia and ultimately death.

In the new study, published in Translational Psychiatry, researchers found that when beta-amyloid destroys a synapse, the nerve cells make more beta-amyloid driving yet more synapses to be destroyed.

"We show that a vicious positive feedback loop exists in which beta-amyloid drives its own production," says senior author Dr Richard Killick from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN). "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."

"Our work uncovers the intimate link between synapse loss and beta-amyloid in the earliest stages of Alzheimer's disease," says lead author Dr Christina Elliott from the IoPPN. "This is a major step forward in our understanding of the disease and highlights the importance of early therapeutic intervention."

The researchers also found that a protein called Dkk1, which potently stimulates production of beta-amyloid, is central to the positive feedback loop. Previous research by Dr Killick and colleagues identified Dkk1 as a central player in Alzheimer's, and while Dkk1 is barely detectable in the brains of young adults its production increases as we age.

Instead of targeting beta-amyloid itself, the researchers believe targeting Dkk1 could be a better way to halt the progress of Alzheimer's disease by disrupting the vicious cycle of beta-amyloid production and synapse loss.

"Importantly, our work has shown that we may already be in a position to block the feedback loop with a drug called fasudil which is already used in Japan and China for stroke." says Dr Killick. "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."

The researchers found that in mice engineered to develop large deposits of beta-amyloid in their brains as they age, just two weeks of treatment with fasudil dramatically reduced the beta-amyloid deposits.

Researchers at King's College London are now seeking funding to run a trial in early stage sufferers of Alzheimer's to determine if fasudil improves brain health and prevents cognitive decline.

Professor Dag Aarsland from the IoPPN said "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. We now need to move this forward to a clinical trial in people with early stage Alzheimer's disease as soon as possible."

Christina Elliott, Ana I Rojo, Elena Ribe, Martin Broadstock, Weiming Xia, Peter Morin, Mikhail Semenov, George Baillie, Antonio Cuadrado, Raya Al-Shawi, Clive G Ballard, Paul Simons, Richard Killick.
A role for APP in Wnt signalling links synapse loss with β-amyloid production.
Translational Psychiatryvolume 8, Article number: 179 (2018). doc: 10.1038/s41398-018-0231-6.

Most Popular Now

Imfinzi is the first immunotherapy to demonstrate …

AstraZeneca and MedImmune, its global biologics research and development arm, have presented data on overall survival (OS) in the Phase III PACIFIC trial of Imfinzi durin...

Sandoz Healthcare Access Challenge #SandozHACk ret…

Sandoz, the Novartis generics and biosimilars division, today announces the launch of the second Sandoz Healthcare Access Challenge (HACk). The #SandozHACk is a global co...

Global survey reveals that physicians need more in…

Results from a new global survey revealed that more than one-third (36%) of the 310 physicians surveyed do not think they have sufficient information required to make inf...

In clinical trials, new antibody therapy controls …

Thanks to improvements in antiretroviral therapy, HIV is now a manageable condition. Yet even the best drugs do not entirely eliminate the virus, which latently lingers i...

Novartis licenses three novel anti-infective progr…

Novartis announced today that it has entered into a licensing and equity agreement with Boston Pharmaceuticals for the development of three novel anti-infective drug cand...

The Nobel Prize in Physiology or Medicine 2018 was…

Cancer kills millions of people every year and is one of humanity's greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor c...

Pfizer to award more than $3 million in grants to …

Pfizer Inc. today announced the recipients of the Advancing Science through Pfizer Investigator Research Exchange (ASPIRE) Breast Cancer Research Awards. Four grants tota...

FDA approves first treatment for advanced form of …

The U.S. Food and Drug Administration today approved Libtayo (cemiplimab-rwlc) injection for intravenous use for the treatment of patients with metastatic cutaneous squam...

DNA islands effective as 'anti-bacterial drones'

Genomic "islands" that evolved from viruses can be converted into "drones" that disable Staphylococcus aureus, bacteria that are often resistant to antibiotics and pose a...

FDA awards 12 grants to fund new clinical trials t…

The U.S. Food and Drug Administration today announced that it has awarded 12 new clinical trial research grants totaling more than $18 million over the next four years to...

Addressing social and cultural drivers of type 2 d…

New research shows healthcare services and public health strategies aimed at reducing the burden of type 2 diabetes may prove ineffective, unless they address social and ...

Evidence mounts linking aspirin to lower risk of o…

Taking a low-dose aspirin daily may help women lower their risk of developing ovarian cancer. A new study co-led by Moffitt Cancer Center found that women who reported ta...