Studies suggest that dementia will affect more than 150 million people around the world by 2050. Alzheimer’s disease can produce a range of symptoms, such as memory loss, cognitive deficits, and changes in personality, which are widely thought to be caused by a buildup of two proteins — beta-amyloid (Aβ) and tau in the brain.
Existing treatments generally aim to alleviate symptoms, with some newer disease-modifying treatments, such as aducanumab and lecanemab, showing promise at clearing Aβ. However, these monoclonal antibody treatments have side effects, which some experts believe may outweigh their clinical benefits.
A new study has outlined a potential treatment that targets the tau protein that builds up into neurofibrillary tangles which slow down the passage of nerve impulses across synapses (the junctions between nerve cells).
The researchers found that in transgenic mice a synthetic peptide, PHDP5, inhibited a pathway that leads to to tau buildup and reversed memory and learning deficits.
The study is published in Brain Research. Key to the transmission of nerve impulses across synapses are two substances — dynamin and microtubules. These work together to recycle vesicles full of neurotransmitters, which transmits the impulse from one nerve cell to the next.
In healthy individuals, tau stabilizes the microtubules. However, in Alzheimer’s the tau separates from microtubules, removes dynamin from the nerve cells, and eventually forms tangles. These changes prevent the effective recycling of vesicles, so nerve impulses are not passed between nerve cells.
In earlier in vitro studies, the researchers had shown that the synthetic peptide PHPD5 released dynamin so that it was available for recycling vesicles, restoring communication between synapses. Doctors say that this research appears to be pioneering in specifically targeting the dynamin-microtubule interaction with the synthetic peptide PHDP5. While other treatments for Alzheimer’s focus on different mechanisms, such as amyloid-beta plaques and tau tangles, targeting the dynamin-microtubule pathway is relatively novel.
The researchers have shown in vitro and in vivo evidence of the positive effects of inhibiting this interaction, suggesting this could be the first time it has been targeted in this manner. Having shown the efficacy of PHPD5 in vitro, the researchers used transgenic Tau609 mice, which develop tau tangles, neuronal loss, and memory loss, for their study. They administered 2mg of PHDP5 in saline solution, into their noses once a day for 4 weeks. Control Tau609 mice were given only saline solution by the same method.
Three weeks into the treatment, they tested the mice’s learning and memory using the Morris Water Maze (MWM) test. The mice were first given four training sessions on finding an escape platform in one quadrant of a 100cm diameter, 30cm deep, circular water trough.
They were then tested in the same trough, without the escape platform. The researchers recorded how much time they spent in the platform quadrant during the test, to determine whether they had remembered where the platform was previously found.
The researchers compared the treated mice with both the control mice and wild-type (WT) mice in terms of their MWM performance.
During training, the WT mice were the best at finding the hidden platform, with 60% reduction in time to reach it after 4 sessions. In comparison, the control Tau609 mice had only a 33% reduction in finding time.
Tau609 mice that were treated with the peptide showed similar results to the WT mice, with a 55% reduction in time by day 4.
On the memory retention test (day 5) when the platform was removed, WT mice spent almost 36% of the time in the quadrant that had formerly had the platform and treated mice spent 33% of their time in this quadrant. The control mice spent only 25% of the time in the platform quadrant.
This indicates that the treated mice had regained learning and memory skills that were absent in the control transgenic mice.
The research on PHDP5 and its potential to reverse cognitive decline in Alzheimer’s is very encouraging and represents a significant advancement in the search for effective treatments.
