3D medical background with female figure with brain highlighted on a background of DNA strands
Credit: kirstypargeter/Getty Images

A team of scientists in Japan has revealed how elevated tau levels impair signaling between neurons in mouse brains. This may point to new approaches to treating Alzheimer’s disease and other neurologic conditions.

The study was published recently in eLife.

Alzheimer’s disease causes neurons to die, slowly destroying memory and thinking skills. It’s the most common type of dementia, impacting an estimated 50 million people worldwide. Despite its prevalence, the causes remain poorly understood and treatment options are limited.

Tau is a key protein produced in neurons that promotes the assembly of microtubules. In some neurological disorders, most famously in Alzheimer’s disease, levels of soluble tau in certain brain regions become too high, and it aggregates into insoluble structures called neurofibrillary tangles. Mutated Tau spreads across the brain.

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

To begin, about ten years ago, Takahashi’s team looked at the effect of high levels of soluble tau on signal transmission at the calyx of Held – the largest synapse in mammalian brains. 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 ‘packets’ called vesicles into the gap between neurons. When the neurotransmitters reach the postsynaptic neuron, they trigger a new electrical signal.

Takahashi’s research team injected soluble tau into the presynaptic terminal at the calyx of Held in mice and found that electrical signals generated in the postsynaptic neuron dramatically decreased. The scientists then fluorescently labelled tau and microtubules and saw that the injected tau caused new assembly of many microtubules in the presynaptic terminal.

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

“This told us that the decrease in synaptic signaling was clearly linked to these newly assembled microtubules,” he said.

A second important clue was that elevated tau only decreased the transmission of high-frequency signals, while 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 might be due to a block on vesicle recycling — a vital process for the release of neurotransmitters across the synapse. If any of the steps in vesicle recycling are blocked, it quickly weakens high-frequency signals, which require the exocytosis of many vesicles.

The scientists found that high levels of soluble tau primarily impaired endocytosis. The lack of reformed vesicles impaired recycling and eventually slowed down exocytosis as a secondary effect. The researchers also found that a drug called nocodazole, which blocks new microtubule assembly, prevented injected tau from impairing endocytosis.

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

The team created many peptides with matching sequences of amino acids to parts of the dynamin protein, to see if any 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 a normal level.


Also of Interest