Excess Tau Protein Interferes in Signaling Between Neurons

Researchers here outline a mechanisms by which the excess tau protein in the brain characteristic of Alzheimer's disease can interfere in the signaling between neurons that is necessary for cognitive function. Interestingly, they also suggest that a very similar mechanism is at play in the accumulation of α-synuclein in conditions such as Parkinson's disease. As always the question is always whether this mechanism is actually a meaningful contribution to the loss of function observed in patients. The brain is very complex, and neurodegenerative conditions are a mess of many, many seemingly harmful mechanisms. As the failure of past efforts to intervene in Alzheimer's disease indicates, not all of those mechanisms are important at any given stage of the condition.

A study has revealed how excess tau - a key protein implicated in Alzheimer's disease - impairs signaling between neurons in the brains of mice. The research began ten years ago, when researchers 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.

Using mice, the research team injected soluble tau into the presynaptic terminal at the calyx of Held 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. 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. Vesicle recycling is a vital process for the release of neurotransmitters across the synapse since 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 reused. If any of the steps in vesicle recycling are blocked, it quickly weakens high-frequency signals, which require the exocytosis of many vesicles.

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, was actually discovered as a protein that binds to microtubules, although little is known about the binding site. When the scientists fluorescently labelled tau, microtubules, and dynamin, they found that presynaptic terminals that had been injected with tau showed an increase of bound dynamin, preventing the protein from carrying out its role in endocytosis. Finally, 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.

Link: https://www.oist.jp/news-center/press-releases/untangling-role-tau-alzheimer%E2%80%99s-disease

Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.