Alzheimer’s-related synapse damage reversed by synthetic protein

A new therapy can reverse Alzheimer’s symptoms in mice, effectively treating cognitive decline and restoring memory.

Researchers at the Okinawa Institute of Science and Technology (OIST) have developed a potentially transformative approach to treating Alzheimer’s disease, A team from the former Cellular and Molecular Synaptic Function Unit have reported significant progress in reversing cognitive decline and restoring memory in transgenic mice using a synthetic protein. The findings, published in Brain Research, offer hope for a viable treatment to alleviate the debilitating symptoms associated with this neurodegenerative condition.

“We successfully reversed the symptoms of Alzheimer’s disease in mice,” explained Dr Chia-Jung Chang, first author of the study and presently a member of the Neural Computation Unit at OIST. “We achieved this with a small, synthetic peptide, PHDP5, that can easily cross the blood-brain barrier to directly target the memory center in the brain [1].”

Longevity.Technology: There is a pressing need to find effective treatments for Alzheimer’s; along with other forms of dementia, this debilitating disease currently affects approximately 55 million people worldwide, and this number is predicted to nearly double every 20 years, reaching 78 million in 2030 and 139 million in 2050. As well as a health burden, Alzheimer’s is an economic burden – the annual global cost of dementia has now rocketed to more than US$ 1.3 trillion, with a projected rise to US$ 2.8 trillion by 2030 on the horizon [2].

While there is an urgent need for advancements in therapeutic interventions for Alzheimer’s, the disease is notoriously difficult to treat; it presents numerous challenges due to its multifaceted etiology involving genetic, environmental and lifestyle factors, and this difficulty is compounded by its progressive nature which often renders treatments less effective once symptoms become apparent.

Central to Alzheimer’s pathology is the health of brain synapses – junctions where neurons communicate through chemical neurotransmitters. This synaptic communication is crucial for cognitive functions and is maintained by the recycling of synaptic vesicles. A protein called dynamin plays a pivotal role in this process, facilitating the final step of vesicle recycling, known as endocytosis. However, in Alzheimer’s, the protein tau, typically involved in stabilizing microtubules within neurons, becomes disassociated, disrupting this process.

During the early stages of Alzheimer’s, tau begins to detach from microtubules, leading to its overassembly into new microtubules, which then sequester dynamin, making it unavailable for endocytosis. As the disease advances, tau accumulates into neurofibrillary tangles – hallmarks of Alzheimer’s that render synaptic repair increasingly difficult and often detectable only when the disease is far advanced.

The research team at OIST, led by Professor Tomoyuki Takahashi, had previously demonstrated the positive effects of inhibiting dynamin-microtubule interaction in vitro using a synthetic peptide named PHDP5. Building on these findings, the team has now shown similar restorative effects in vivo using transgenic mice. By inhibiting the interaction between dynamin and microtubules, PHDP5 preserves the synaptic function essential for learning and memory [3].

“By preventing the interaction between dynamin and microtubules, PHDP5 ensures that dynamin is available for vesicle endocytosis during recycling, which can restore the lost communication between neurons inside the synapses at an early stage,” said Dr Zacharie Taoufiq, second author of the paper [1].

“We were thrilled to see that PHDP5 significantly rescued learning and memory deficits in the mice,” added Chang. “This success highlights the potential of targeting the dynamin-microtubule interaction as a therapeutic strategy for Alzheimer’s disease [1].”

Having a nose for success

To enhance the peptide’s efficacy, the researchers modified PHDP5 to include a cell-penetrating component, facilitating its delivery through the nasal cavity. This method leverages the relatively underdeveloped blood-brain barrier in this region, allowing higher concentrations of PHDP5 to reach the hippocampus – the brain’s memory center – while minimizing systemic side effects.

In their experiments, the researchers found that early intervention with PHDP5 could reverse synaptic damage caused by Alzheimer’s, resulting in learning and memory abilities in treated mice comparable to those of healthy mice. While PHDP5 does not cure Alzheimer’s, it significantly delays cognitive decline to the extent that symptoms may not manifest within a typical human lifespan if treated early [3].

Despite the encouraging results, the journey from laboratory research to an approved drug is arduous and can often be measured in decades rather than years; however, the rapid development of COVID-19 vaccines has renewed optimism about accelerating the transition from research findings to clinical application.

The OIST team is continuing to refine PHDP5 and its delivery mechanisms, while simultaneously navigating the extensive production and regulatory pipelines necessary for drug development.

 “We want to increase the amount of PHDP5 in the brain to achieve better effects, while minimizing side effects,” Taoufiq commented, adding that the team is working with the university’s Innovation division to move the peptide through the production pipeline. “We want to involve pharmaceutical companies going forward,” he said. “They have the necessary expertise in pharmacology and the capacity for human trials to turn our peptide into a viable treatment [1].”

Citing the coronavirus vaccine development, Chang said: “We don’t expect this to go as quickly, but we know that governments – especially in Japan – want to address Alzheimer’s disease, which is affecting so many people. And now, we have learned that it is possible to effectively reverse cognitive decline if treated at an early stage [1].”

[1] https://www.oist.jp/news-center/news/2024/6/20/damage-synapses-caused-alzheimers-disease-reversed
[2] https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/
[3] https://www.sciencedirect.com/science/article/pii/S0006899324002415?via%3Dihub