A New Nasal Spray Reverses Memory Loss in Alzheimer’s Mice, Study Finds

31 December 2024
by: Juicing For Health
in Lifestyle & Wellness

Last updated on

Something unusual happened in a Japanese laboratory when mice with Alzheimer’s disease started remembering again. Scientists at the Okinawa Institute of Science and Technology have developed a synthetic peptide that reversed cognitive decline in mouse models of Alzheimer’s disease. No human trials have taken place yet, and years of testing remain before patients could access such a treatment. But early results from mouse studies, published in Brain Research, suggest researchers may have found a way to rescue brain function before permanent damage sets in. Alzheimer’s disease has long resisted treatment. By the time symptoms appear, the brain has often deteriorated beyond repair. Most therapies focus on slowing decline rather than reversing it. Yet a team led by Professor Emeritus Tomoyuki Takahashi has taken a different approach, targeting the disease at a molecular level that scientists had previously overlooked. Their findings raise a tantalizing question. What if memory loss could be undone?

A Disease That Defies Treatment

Alzheimer’s disease affects an estimated 55 million people around the world. In Japan alone, roughly 4.4 million people live with dementia, and government projections suggest that number will climb to 6.5 million by 2060. Families watch loved ones fade, losing first their recent memories, then their ability to perform daily tasks, and eventually their recognition of the people closest to them. Finding effective treatments has proven extraordinarily difficult. Multiple factors appear to contribute to the disease, from genetics to lifestyle choices. No single cause has been identified. And because Alzheimer’s progresses slowly and silently, patients often receive diagnoses only after significant brain damage has already occurred. At that point, interventions can do little more than manage symptoms. Researchers have spent decades trying to crack this puzzle. Many promising treatments have failed in clinical trials. Yet the OIST team believed they had identified a mechanism that earlier efforts had missed.

Synapses Under Siege

Brain cells communicate through structures called synapses, tiny gaps where one neuron passes information to the next. Chemical messengers called neurotransmitters carry signals across these gaps, packaged inside small bubbles known as vesicles. For communication to continue smoothly, cells must constantly recycle these vesicles. A protein called dynamin handles one of the final steps in this recycling process. It pinches off vesicles from cell membranes so they can be refilled and reused. Without enough available dynamin, the recycling process breaks down. Communication between neurons falters. Here is where Alzheimer’s disease enters the picture. Another protein called tau normally helps stabilize the internal scaffolding of brain cells. But in early Alzheimer’s, tau begins to detach from this scaffolding. Once free, tau starts building new scaffolding structures at an excessive rate. And dynamin gets trapped on these new structures, leaving too little available for vesicle recycling. As the disease progresses, loose tau proteins clump together into tangles. By the time these tangles appear on brain scans, treatment options have narrowed considerably. But the OIST researchers wondered whether intervening earlier, before tangles formed, might preserve brain function.

A Peptide Called PHDP5

Dr. Chia-Jung Chang, first author of the study and a member of the Neural Computation Unit at OIST, worked with colleagues to develop a small synthetic peptide they named PHDP5. Its job is simple in concept but powerful in effect. PHDP5 blocks the interaction between dynamin and the cell’s internal scaffolding, freeing dynamin to perform its essential recycling work. “We successfully reversed the symptoms of Alzheimer’s disease in mice,” Dr. Chang explained. “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.” Previous work had shown PHDP5 could restore normal function in brain tissue samples. Now the team needed to test whether it would work in living animals.

Why a Nasal Spray?

Getting drugs into the brain presents a major challenge. A protective system called the blood-brain barrier filters out most substances that circulate in the bloodstream. Many potential treatments fail simply because they cannot reach their target. PHDP5 is small enough to cross this barrier, but the researchers wanted to maximize delivery to the hippocampus, the brain’s memory center. They modified the peptide with an additional component that helps it penetrate cells and chose nasal administration as their delivery method. The blood-brain barrier is less developed in the nasal cavity. And the distance from the nose to the hippocampus is short. Nasal delivery allowed higher concentrations of the peptide to reach the target area while keeping levels low elsewhere in the body, reducing the risk of side effects.

Mice That Remembered Again

Alzheimer’s Breakthrough: New Peptide Treatment Reverses Cognitive Decline
byu/Hashirama4AP inEverythingScience
Researchers tested PHDP5 on two different mouse models of Alzheimer’s disease. Tau609 mice carry a human tau gene mutation and develop memory problems around six months of age. 3xTg-AD mice carry three different mutations associated with Alzheimer’s and show similar cognitive decline. After four weeks of treatment via nasal spray, mice underwent testing in a Morris Water Maze. Animals were placed in a pool of water and trained to find a hidden platform using visual cues around the room. Healthy mice learn the platform’s location quickly and remember it well. Mice with Alzheimer’s struggle with both learning and memory. Results proved striking. Untreated Alzheimer’s mice and those receiving a scrambled control peptide showed poor performance, taking much longer to find the platform and spending less time in the correct area during memory tests. But mice treated with PHDP5 performed nearly as well as healthy animals. “We were thrilled to see that PHDP5 significantly rescued learning and memory deficits in the mice,” Dr. Chang said. “This success highlights the potential of targeting the dynamin-microtubule interaction as a therapeutic strategy for Alzheimer’s disease.” Double-blind tests, in which researchers did not know which treatment each mouse received, confirmed the results. PHDP5 did not enhance performance in healthy mice, ruling out a general cognitive boost. Instead, it appeared to rescue specifically the functions that Alzheimer’s had impaired.

What PHDP5 Cannot Do

Important limitations apply to these findings. PHDP5 does not cure Alzheimer’s disease. It does not eliminate tau or prevent tangles from forming. Rather, it appears to work around the problem, keeping dynamin available for its normal job despite the presence of excess tau. For this workaround to succeed, treatment must begin early, before extensive damage has occurred. Once neurons die, no peptide can bring them back. PHDP5 offers a way to preserve function, not to resurrect what has been lost. Potential side effects also warrant attention. The interaction between dynamin and cell scaffolding serves purposes throughout the body, including in kidney function. Widespread suppression of this interaction could cause problems. Nasal delivery helps limit systemic exposure, but researchers will need to study long-term effects carefully.

From Mice to Medicine

Animal studies do not always translate to human treatments. Many therapies that work in mice fail when tested in people. The path from laboratory discovery to approved medicine is long, expensive, and littered with disappointments. Dr. Zacharie Taoufiq, based in the Synapse Biology Unit at OIST and second author of the paper, continues working to improve the peptide itself. His goal is to increase concentrations in the brain while further reducing any unwanted effects elsewhere. “We want to involve pharmaceutical companies going forward,” Dr. Taoufiq explained. “They have the necessary expertise in pharmacology and the capacity for human trials to turn our peptide into a viable treatment.” OIST’s Innovation Division has begun moving the peptide through early stages of commercial development. But human trials remain years away, and the full journey from discovery to prescription averages about 20 years.

Grounds for Hope

Despite the long road ahead, researchers express cautious optimism. Dr. Chang points to recent history for encouragement. “The coronavirus vaccine showed us that treatments can be rapidly developed, without sacrificing scientific rigor or safety. 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.” Professor Emeritus Takahashi, who started the project before his retirement, has called for pharmaceutical companies to take the peptide through human clinical trials. He hopes that PHDP5 might reach patients without excessive delay and help rescue the cognitive symptoms that matter most to those living with the disease. For now, mice in an Okinawa laboratory continue to find hidden platforms and remember where they are. Whether humans will one day benefit from the same treatment remains an open question, but science has taken one more step toward answering it. Study citation: Chang, C.J., Taoufiq, Z., Yamada, H., et al. “The microtubule-dynamin binding inhibitor peptide PHDP5 rescues spatial learning and memory deficits in Alzheimer’s disease model mice.” Brain Research (2024). https://doi.org/10.1016/j.brainres.2024.14898

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