Unraveling the role of tau in Alzheimer’s disease


  • A new study has revealed how tau – a microtubule-binding protein implicated in Alzheimer’s disease – weakens transmission across synapses in the brains of mice
  • When injected into presynaptic terminals, tau assembles many new microtubules
  • The excess of newly assembled microtubules impairs endocytosis – a vital process that reshapes synaptic vesicles necessary for transmission
  • The blockage of endocytosis occurs because dynamin, a protein with a key role in endocytosis, binds to the excess microtubules and is unable to function
  • The study also showed that a small peptide called PHDP5 could be a potential new tool for the treatment of Alzheimer’s disease as it stops dynamin binding to the microtubules, returning transmission across synapses to a near normal. level is restored.

Press release

Alzheimer’s disease is a brain disorder that causes neurons to die, slowly destroying memory and thinking. It is the most common form of dementia, affecting an estimated 50 million people worldwide, and is a particularly serious problem for the super-aging Japanese society. Despite its prevalence, the causes remain poorly understood and treatment options are limited.

Now, a team of scientists in Japan has revealed how excess tau — a key protein implicated in Alzheimer’s disease — hinders signaling between neurons in mouse brains. The study, recently published in eLifecould open new avenues for treating the symptoms and even halting the progression of Alzheimer’s disease and other neurodegenerative disorders.

Tau is produced in neurons, where it binds to and promotes the assembly of microtubules – long, thin filaments that maintain cell structure and provide transport pathways within the cell. Tau usually exists in this bound state, or it is dissolved in the liquid that fills the cell.

However, in some neurological disorders, most commonly known in Alzheimer’s disease, the levels of soluble tau in certain brain regions become too high and aggregate into insoluble structures called neurofibrillary tangles.

“Many scientists focus on the impact of these visible neurofibrillary tangles that are characteristic of Alzheimer’s disease, but actually it is the invisible levels of soluble tau that most correlate with cognitive decline,” said Professor Tomoyuki Takahashi, senior author of the study. research. , and head of the Cellular and Molecular Synaptic Function Unit at OIST.

The research began a decade ago, when his team looked at the effect of high levels of soluble tau on signal transmission in Held’s calyx — the largest synapse in the mammalian brain. Synapses are the places where two neurons make contact and communicate. When an electrical signal arrives at the end of a presynaptic neuron, chemical messengers known as neurotransmitters are released from membrane ‘packages’ called vesicles in the gap between neurons. When the neurotransmitters reach the postsynaptic neuron, they activate a new electrical signal.

When an electrical signal arrives at the presynaptic terminal, neurotransmitters are released from vesicles in the gap between neurons. The neurotransmitters then trigger an electrical signal in the postsynaptic neuron.

Using mice, Prof. Takahashi’s research team injected soluble tau into the presynaptic terminal at Held’s calyx and found that electrical signals generated in the postsynaptic neuron decreased dramatically.

The scientists then fluorescently labeled tau and microtubules and saw that the injected tau caused reassembly of many microtubules in the presynaptic terminal.

However, when they instead injected a mutant tau protein that lacked the binding site needed to assemble microtubules, there was no effect on synaptic transmission.

“This told us that the decrease in synaptic signaling was clearly related to these newly assembled microtubules,” explains Prof. Takahashi.

A second important clue was that increased tau only reduced the transmission of high-frequency signals, while the low-frequency transmission remained unchanged. High-frequency signals are typically involved in cognition and movement control.

The researchers suspected that such a selective impact on high-frequency transmission could be due to a blockage in vesicle recycling.

Vesicle recycling is an essential process for the release of neurotransmitters from the synapse, as synaptic vesicles must fuse with the presynaptic terminal membrane, in a process called exocytosis. These vesicles are then reformed by endocytosis and refilled with neurotransmitter to be used again. If one of the steps in vesicle recycling is blocked, it quickly attenuates high-frequency signals, which require the exocytosis of many vesicles.

Exocytosis and endocytosis are important steps in vesicle recycling. Exocytosis increases the surface area of ​​the presynaptic terminal membrane and endocytosis decreases its surface area, so by electrically measuring the surface area of ​​the terminal membrane, scientists can determine whether any of these steps are impaired.

The scientists found that high levels of soluble tau primarily worsened endocytosis. The lack of reformed vesicles impeded recycling and ultimately delayed exocytosis as a secondary effect.

Importantly, the researchers found that a drug called nocodazole, which blocks the new assembly of microtubules, prevented injected tau from impairing endocytosis.

The next step for the researchers was to find out exactly how an excess of microtubules caused a blockage of endocytosis.

While looking for a link between microtubules and endocytosis, the team realized that dynamin, a large protein that cuts vesicles from the surface membrane at the final step of endocytosis, was actually discovered as a protein that binds to microtubules, although little is known. about the binding site.

When the scientists fluorescently labeled tau, microtubules and dynamin, they found that presynaptic ends injected with tau showed an increase in bound dynamin, preventing the protein from fulfilling its role in endocytosis.

Finally, the team created many peptides with matching amino acid sequences to parts of the dynamin protein, to see if one of them could prevent dynamin from binding to the microtubules, and therefore rescue the signaling defects caused by tau protein. When one of these peptides, called PHDP5, was injected along with tau, endocytosis and synaptic transmission remained close to normal levels.

The peptide, PDHP5, prevents injected tau from impairing endocytosis and synaptic transmission.

In the future, the researchers plan to test this peptide in Alzheimer’s mouse models with elevated levels of soluble tau. These mice lose their ability to learn and form new memories around 6-8 months of age, and the team hopes the peptide can prevent or reverse this memory impairment.

“For this we need to adapt PHDP5 so that it can cross the blood-brain barrier. If this peptide works in these mouse models, it could serve as an effective therapeutic tool for Alzheimer’s disease,” said Prof. Takahashi.

research article

Title: The assembly of microtubules by tau impairs endocytosis and neurotransmission via dynamine sequestration in the synapse model of Alzheimer’s disease

Magazine: eLife

Authors: Tetsuya Hori, Kohgaku Eguchi, Han-Ying Wang, Tomohiro Miyasaka, Laurent Guillaud, Zacharie Taoufiq, Satyajit Mahapatra, Hiroshi Yamada, Kohji Takei, Tomoyuki Takahashi

Date: April 26, 2022

DOI: 10.7554/eLife.73542

#Unraveling #role #tau #Alzheimers #disease

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