Tau: A New Way To Deal With Autism and Epilepsy

Tau: A New Way To Deal With Autism and Epilepsy ...

Children with Dravet syndrome, a severe form of epilepsy that starts in early life, have seizures throughout their entire life. They are at a high risk of unexpected death in epilepsy (SUDEP) and may also develop intellectual disability and autism. Typically, medicines do not improve these symptoms.

A group of scientists at Gladstone Institutes, led by Dr. Lennart Mucke, has revealed new findings in the journalScience Translational Medicine that might guide the development of better therapeutic strategies for Dravet syndrome.

In a mouse model of Dravet syndrome, scientists discovered that genetically removing the protein tau from the entire body during embryonic development reduced epilepsy, SUDEP, and autism-like behaviors. In the study, they identified the key cell type in the brain in which tau levels must be reduced to avoid these difficulties. However, they demonstrated that lowering tau is still effective in mice when the intervention is delayed until after their birth.

A team of scientists led by Mucke (left) and Eric Shao (right) discovered a promising treatment strategy that would be beneficial for Dravet syndrome, epilepsy, autism, and Alzheimer''s disease.

These findings provide new insights into the cellular pathways by which tau reduction prevents abnormal overexcitation in the brain. These findings are also encouraging from a therapeutic perspective, as in humans, initiating therapy after birth is still more feasible than treating embryos in the womb.

Tau is a promising therapeutic target non only for Dravet syndrome, but also for a wide range of other conditions, including certain types of epilepsy and some forms of autism, as well as Alzheimers disease and related neurodegenerative diseases.

Pinpointing the Crucial Brain Cells

The correct balance between excitatory and inhibiting neurons is needed for a healthy brain, while the latter stimulates the activity of other neurons. Dravet syndrome has resulted in an abnormally high and synchronized activity in brain networks that can manifest as seizures and other symptoms.

Mucke and his colleagues have recently shown that removing tau from the entire brain alters the activities of both excitatory and inhibitory neurons, although in different ways. The present study aimed to determine whether it is more important to reduce tau in excitatory or inhibitory neurons.

In the Dravet mouse experiment, scientists used genetic tools to remove tau from one or the other cell type. They found that removing tau from excitatory neurons reduced disease manifestations, whereas removing tau from inhibitory neurons did not.

According to Mucke, who is a Distinguished Professor of Neuroscience at the University of San Francisco, tau production in excitatory neurons sets the stage for all of these abnormalities, including autistic behavior, epilepsy, and sudden unexpected death.

Initiating Treatment after Birth

The scientists employed synthetic tau to remove tau from specific cell types are effective and precise, but they aren''t yet straightforward to describe as a therapeutic therapy in humans. So, the team found out that 100 days after birth, an anti-tau ASO was found to have gone four months later.

According to Eric Shao, the PhD student who works in the Muckes lab and the first author, we observed a moderate reduction of SUDEP, seizures, and repetitive behaviors.

ASO treatment had no obvious side effects.

At the same time, Gladstone scientists discovered that worldwide reducing tau in the brain with an ASO reduced the most symptoms of Dravet syndrome. Shao examines sections of the mouse brain to see if the anti-tau ASO penetrated all parts of the brain.

This is especially true since a Phase I clinical trial in people with Alzheimers disease has already begun, according to Mucke. It might be beneficial to consider this approach also for Dravet syndrome and related conditions. However, determining the appropriate timing for treatment initiation will be crucial, as the chance of success may be narrow.

Although Alzheimers disease, epilepsy, and autism are a variety of problems, they all appear to be associated with abnormally high levels between excitatory and inhibiting neuronal activity, and this abnormality might be mitigated by tau-lowering therapies.

Despite the fact that steroids would be used as a tablet, some people prefer to avoid repeated spinal taps. Mucke is working with Takeda Pharmaceuticals to develop small molecules that could reduce brain tau levels.

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