Studies in mouse models have shown how reducing levels of tau, a protein linked with Alzheimer’s disease (AD), could prevent core symptoms of autism spectrum disorder (ASD). Tau has never before been linked with autism, but the newly reported studies by a team at the Gladstone Institute of Neurological Disease, showed that reducing levels of tau in mouse models that mirror different forms of ASD also prevented seizures, which occur in 30% of people with autism.

“Our findings suggest that tau reduction holds promise as a potential treatment for some forms of autism,” said Lennart Mucke, MD, the founding director of the Gladstone Institute of Neurological Disease, and senior author of the team’s published paper in Neuron. “We’ve uncovered an unexpected new connection between degenerative diseases of aging and developmental disorders of childhood.” Mucke, who is also a professor of neurology and neuroscience at the University of California, San Francisco, and colleagues, described their findings in a paper titled, “Tau Reduction Prevents Key Features of Autism in Mouse Models.”

Approximately 1% of the world’s population is thought to have an ASD, the authors wrote. “Diagnosis of these conditions has increased sharply over the last few decades, and their economic cost in 2015 was estimated at $268 billion in the United States alone.” While autism manifests in myriad forms, with symptoms and severity varying widely from person to person, the three common, core symptoms include “… repetitive behaviors, impaired social interactions, and communication deficits,” the team noted. Patients may in addition display epilepsy, intellectual disability, hyperactivity, anxiety-related behaviors, delayed psychomotor development, attention deficits, gastrointestinal disturbances, or sleep disorders. New treatments are urgently needed, the authors pointed out, as the two drugs approved by FDA for treating ASD offer “little or no benefit” for the core symptoms, “ … highlighting the need for additional therapeutic strategies.” And the 30% or so of ASD patients who suffer from epileptic seizures may derive little or no benefit from existing anti-epileptic drugs.

Mucke’s team had previously shown that genetically reducing tau can prevent or lessen epilepsy that results from a variety of causes, including a mouse model of Dravet syndrome, which is a severe, treatment-resistant seizure disorder of early-childhood onset that is often associated with signs of autism. “Because tau reduction suppresses not only epilepsy and seizure-related sudden death in these mice but also learning and memory deficits, we hypothesized that it would also mitigate their autism-like phenotype,” the authors noted. “We wondered whether tau reduction could also prevent the signs of autism that are often seen in people with Dravet syndrome,” said first author Chao Tai, PhD, a scientist in Mucke’s team who had previously studied Dravet syndrome at the University of Washington.

To explore this possibility further, the team studied the effects of deleting either one or both copies of the gene that encodes tau, in a mouse model of Dravet syndrome. They found that tau reduction prevented the development of core autism symptoms in the animals model. Even a 50% reduction in tau was linked with a reduction in core ASD-related symptoms. Reducing tau in a second mouse model of autism that results from a very different genetic mutation also led to significant reduction in autism-related behaviors. “… it also worked beautifully,” Tai said. “The autism-like behaviors were again strongly suppressed by tau reduction.”

Further studies showed that Tau reduction prevented two additional abnormalities seen in people with autism and related mouse models, an enlargement of the brain known as megalencephaly, and over-activation of the PI3K-Akt-mTOR signaling pathway, which regulates many important cell functions.

“All of these abnormalities were prevented or markedly diminished by partial or complete genetic removal of tau,” the team noted. Studies, in addition, showed that Tau reduction prevented ASD-related neural changes in both the mouse models. “Thus, in independent models of ASD, tau is required not only for the development of autism-like behaviors but also for the development of neural alterations that may cause or contribute to these behaviors,” the team noted. “Tau reduction counteracts all of these abnormalities.”

In a final series of tests, the researchers investigated the molecular mechanisms by which tau reduction might prevent autism-related abnormalities. They found that reducing tau enhanced PTEN activity, which can prevent overactivation of the autism-promoting signaling pathway. “These data suggest that tau and tau reduction regulate the PI3K signaling pathway indirectly by modulating the activity of PTEN,” they wrote. “Our findings support the hypothesis that tau enables the development of some ASDs by curtailing the activity of PTEN, a physiological function that, under pathological conditions, may allow ASD-promoting factors to overactivate the PI3K/Akt/mTOR pathway.”

Gladstone researchers Lennart Mucke, MD, and Chao Tai, PhD, discovered a potential role for the Alzheimer’s disease-related protein tau in autism spectrum disorders. [Lauren Bayless, Gladstone Institutes]
The authors acknowledged that tau reduction is unlikely to be an effective therapeutic strategy for every form of autism. Nevertheless, they suggested, the new findings highlight the potential of tau reduction to counteract both neurologic and psychiatric disorders. ” … we discovered a surprising role of tau in ASD pathogenesis that extends the impact of this intriguing protein from age-related neurodegenerative diseases to neurodevelopmental disorders … This study shows that the development of ASD-relevant behavioral, anatomical, and biochemical abnormalities in two mouse models that simulate distinct causes of ASD critically depends on tau levels, requiring >50% of physiological tau levels found in WT mice.”

Mucke further noted, “Tau reduction appears to be the first strategy that can prevent both autism and epilepsy, two challenging conditions that all too often afflict the same people.” Tai added, “Autism is very frequent, affecting roughly one in 60 children. Our findings could help address the urgent need for the development of better therapeutic strategies.”

The results indicated that the molecular changes that cause autism may likely affect the brain during early stages of development and well before a diagnosis is typically made. “We are therefore eager to investigate whether tau reduction can also reverse symptoms of autism after they have emerged,” Mucke said. “Ongoing studies in experimental models should help clarify optimal times for administering tau-lowering drugs to prevent or treat symptoms.” Mucke and colleagues are developing and testing small-molecule drugs that could lower tau levels or increase the activity of PTEN. Other investigational tau-lowering approaches are already being tested in people as a potential treatment for Alzheimer’s disease, and this new research suggests that findings from those trials may also be informative for autism research. “A clinical trial of a tau-lowering antisense oligonucleotide is underway in patients with early Alzheimer’s disease (NCT03186989). However, additional studies are needed to fully explore the therapeutic potential and safety of tau reduction in neurodevelopmental disorders.”

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