Lowering levels of tau protein improved multiple symptoms of autism spectrum disorders (ASD) in two different mouse models of the disease, both of which are driven by hyperactivity of the mTOR PI3 kinase pathway.

The findings link tau, which is best known as public enemy number two in Alzheimer’s disease (AD), to ASD – a surprising finding, Lennart Mucke told BioWorld, seeing as “there were no genetic clues… There are so many genes that have been implicated in autism, but tau isn’t one of them.”

Mucke is the founding director of the Gladstone Institute of Neurological Disease, a member institution of the Gladstone Institutes. He is also a professor of neurology and neuroscience at the University of California, San Francisco. He and his colleagues reported their results in the March 2, 2020, issue of Neuron.

For Mucke and his team, the realization that tau might play a role in ASD was “kind of a gradual discovery,” he said.

The team was interested in the role of tau in regulating neural network activity, and had shown that reducing tau prevented the development of abnormal network activity in mouse models of AD.

During those experiments, the team also noticed that “somehow, when you reduce tau levels in the brain, even just by half, they become much more resistant to epilepsy,” Mucke said.

Epilepsy is a large-scale neurological problem in its own right, affecting 3 million adults and nearly half a million children in the U.S.

But it also frequently coexists with other diseases. For example, 40% of AD patients may have subclinical epilepsy, and roughly 30% of people with ASD have some form of epilepsy.

Tau + mTOR = trouble

Mucke and his colleagues decided to test whether lowering tau protein could ameliorate epilepsy outside of the context of AD, where levels are high and tau is aggregated.

They tested the effects of lowering tau in a mouse model of Dravet syndrome, a childhood onset, very severe form of epilepsy – affected individuals can have more than 100 seizures a day – that frequently co-occurs with symptoms of autism.

In a mouse model of that syndrome, researchers reduced tau levels by knocking out one or both copies of the MAPT gene, which codes for tau. That manipulation not only reduced seizure activity in Dravet syndrome animals, “it also very effectively prevented the core symptoms of autism,” Mucke said. On the behavioral level, those core symptoms are impaired social interactions, communication deficits and excessive repetitive behaviors.

Delving into the molecular underpinnings of that prevention, the team found that tau reduction was effective in an additional mouse model of ASD created by knocking out the CNTNAP2 gene, but not in a third, the Shank3 model.

The ASDs those models simulate have very different causes. Dravet syndrome is most often caused by a dysfunctional sodium channel, while CNTNAP2 codes for neurexin, which is important for establishing synapses during development – both mutations ultimately lead to hyperactivation of the mTOR-PI3 kinase pathway. Shank3 mutations do not overactivate that pathway.

Furthermore, the team showed that releasing the power of PTEN, which is best known as a tumor suppressor, can prevent overactivation of the mTOR-PI3k pathway. Reducing tau levels upped PTEN activity and quieted the mTOR pathway.

“We found a choke point in distinct forms of autism that have very different initiating causes but share overactivation of the mTOR-PI3k pathway, a disease-causing driver that tau reduction can block,” Mucke said.

Tau’s contribution in ASD is not that it “has assumed a toxic property, or accumulates like it does in Alzheimer’s disease,” he said. “In ASD, there is a need for a stronger brake” on the mTOR-PI3k pathway, which reducing tau levels provides via unleashing the power of PTEN.

The findings suggest multiple potential strategies for preventing the core behavioral symptoms of ASD – something that none of the available treatments are able to do. The approved treatments primarily aim to suppress anxiety and irritability or other symptoms of ASD.

Mucke and his group are “actively engaged” in the discovery of small-molecule reducers of tau, he said. His team is also using antisense oligonucleotides (ASOs) against tau to test whether lowering tau can reverse ASD symptoms once the abnormal circuits underlying the symptoms have been established, or whether lowering tau works only as prevention, which would make its application a more difficult proposition, at least in the near term.

If it works, treatment might turn out to be easily translatable due to a parallel development. The anti-tau ASO IONIS-MAPTRx (BIIB-080, Ionis Pharmaceuticals Inc./Biogen Inc.) is in a phase I trial for AD.

Mucke said that a potential advantage of targeting tau, rather than PTEN, mTOR or PI3k, is that lowering tau “just seems to prevent abnormal overactivation of mTOR-PI3K, but it doesn’t inhibit the baseline function of this pathway.”

The mTOR complex is a keystone that integrates nutrient sensing with cellular growth decisions, and has the multiple regulators one would expect from that role.

“When you manipulate a pathway that has so many regulators, some entry points may be particularly effective and well-tolerated,” Mucke said. Targeting tau “leaves alone some mTOR functions that you wouldn’t want to inhibit.”

Another advantage is that tau lowering prevented epilepsy as well as the core behavioral symptoms of ASD. “I am not aware of any other treatment that can achieve the same feat,” he said.

That said, rapamycin has been tested in models of autism and has shown some promise, and Mucke acknowledged that “there are clearly additional entry points upstream of mTOR… there is interesting target and drug discovery to be had.”

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